Solid state forms

ABSTRACT

The present disclosure provides crystalline and amorphous forms of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one, including several anhydrous, hydrate and solvate forms, and solid state forms thereof, pharmaceutical compositions, and methods of treating a disease mediated by KRAS G12C inhibition.

CROSS REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/851,044, filed on May 21, 2019, which is incorporated by referenceherein in its entirety.

FIELD

The present disclosure provides a crystalline form of6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one,(hereinafter “Compound 1”), including several crystalline forms of ananhydrous form, a hydrate form, several solvate forms, and physicalforms thereof, pharmaceutical compositions, and a method of treating adisease mediated by KRAS G12C inhibition.

BACKGROUND

Compound 1 is a selective inhibitor of KRAS G12C useful for thetreatment of cancers, including treatment of lung cancer, such asnon-small cell lung cancer (NSCLC), pancreatic cancer, and colorectalcancer. United States Patent Application Publication Number2018/0334454A1, published on Nov. 22, 2018, discloses Compound 1.

Many compounds can exist in different crystal forms, or polymorphs,which exhibit different physical, chemical, and spectroscopicproperties. For example, certain polymorphs of a compound may be morereadily soluble in particular solvents, may flow more readily, or maycompress more easily than others. See, e.g., P. DiMartino, et al., J.Thermal. Anal., 48:447-458 (1997). In the case of drugs, certain solidforms may be more bioavailable than others, while others may be morestable under certain manufacturing, storage, and biological conditions.This is particularly important from a regulatory standpoint, since drugsare approved by agencies such as the U.S. Food and Drug Administrationonly if they meet exacting purity and characterization standards.Indeed, the regulatory approval of one polymorph of a compound, whichexhibits certain solubility and physico-chemical (includingspectroscopic) properties, typically does not imply the ready approvalof other polymorphs of that same compound.

Polymorphic forms of a compound are known in the pharmaceutical arts toaffect, for example, the solubility, stability, flowability,fractability, and compressibility of the compound, as well as the safetyand efficacy of drug products comprising it. See, e.g., Knapman, K.Modern Drug Discoveries, 2000, 53. Therefore, the discovery of newpolymorphs of a drug can provide a variety of advantages.

The present disclosure provides new polymorphic forms of Compound 1,including several crystalline forms of an anhydrous form, a hydrateform, several solvate forms, and physical forms thereof, pharmaceuticalcompositions, and a method of treating a disease mediated by KRAS G12Cinhibition. The new polymorphic forms can further the development offormulations for the treatment of these chronic illnesses, and may yieldnumerous formulation, manufacturing and therapeutic benefits.

SUMMARY

The present disclosure provides crystalline and amorphous forms of6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one,including several anhydrous, hydrate and solvate forms, and solid stateforms thereof, pharmaceutical compositions, and methods of treating adisease mediated by KRAS G12C inhibition.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows XRPD data for an amorphous form of Compound 1. The powderX-ray pattern is characteristic of amorphous material with a broadamorphous halo and no distinct compound related diffraction peaks from5-40° 2-theta.

FIG. 2 shows DSC data for an amorphous form of Compound 1.

FIG. 3 shows TGA data for an amorphous form of Compound 1.

FIG. 4 shows ¹⁹F solid state NMR (SSNMR) for an amorphous form ofCompound 1.

FIG. 5 shows XRPD data for the crystalline anhydrous form I ofCompound 1. The powder X-ray diffraction pattern of the anhydrous formsI-III of Compound 1 is characteristic of crystalline material withdistinct diffraction peaks between 3° 2-theta to 40° 2-theta.

FIG. 6 shows DSC data for crystalline anhydrous form I of Compound 1.

FIG. 7 shows TGA data for crystalline anhydrous form I of Compound 1.

FIG. 8 shows ¹³C SSNMR data for crystalline anhydrous form I of Compound1.

FIG. 9 shows ¹⁹F SSNMR data for crystalline anhydrous form I of Compound1.

FIG. 10 shows XRPD data for the crystalline anhydrous form II ofCompound 1.

FIG. 11 shows DSC data for crystalline anhydrous form II of Compound 1.

FIG. 12 shows TGA data for crystalline anhydrous form II of Compound 1.

FIG. 13 shows ¹³C SSNMR data for crystalline anhydrous form II ofCompound 1.

FIG. 14 shows ¹⁹F SSNMR data for crystalline anhydrous form II ofCompound 1.

FIG. 15 shows XRPD data for the crystalline anhydrous form III ofCompound 1.

FIG. 16 shows DSC data for crystalline anhydrous form III of Compound 1.

FIG. 17 shows TGA data for crystalline anhydrous form III of Compound 1.

FIG. 18 shows XRPD data for the crystalline hydrate form of Compound 1.

FIG. 19 shows DSC data for the crystalline hydrate form of Compound 1.

FIG. 20 shows TGA data for the crystalline hydrate form of Compound 1.

FIG. 21 is the overlay XRPD data (from top to bottom) for thecrystalline anhydrous forms I, II, and III and the crystalline hydrateform of Compound 1.

FIG. 22 shows XRPD data for the crystalline THF Solvate Form I ofCompound 1.

FIG. 23 shows DSC data for the crystalline THF Solvate Form I ofCompound 1.

FIG. 24 shows TGA data for the crystalline THE Solvate Form I ofCompound 1.

FIG. 25 shows XRPD data for the crystalline MeCN Solvate Form I ofCompound 1.

FIG. 26 shows DSC data for the crystalline MeCN Solvate Form I ofCompound 1.

FIG. 27 shows TGA data for the crystalline MeCN Solvate Form I ofCompound 1.

FIG. 28 shows XRPD data for the crystalline MEK Solvate Form I ofCompound 1.

FIG. 29 shows DSC data for the crystalline MEK Solvate Form I ofCompound 1.

FIG. 30 shows TGA data for the crystalline MEK Solvate Form I ofCompound 1.

FIG. 31 shows XRPD data for the crystalline EtOAc Solvate Form I ofCompound 1.

FIG. 32 shows XRPD data for the crystalline DMF Solvate Form I ofCompound 1.

FIG. 33 shows DSC data for the crystalline DMF Solvate Form I ofCompound 1.

FIG. 34 shows TGA data for the crystalline DMF Solvate Form I ofCompound 1.

FIG. 35 shows XRPD data for the crystalline DCM Solvate Form I ofCompound 1.

FIG. 36 shows DSC data for the crystalline DCM Solvate Form I ofCompound 1.

FIG. 37 shows TGA data for the crystalline DCM Solvate Form I ofCompound 1.

FIG. 38 shows XRPD data for the crystalline Acetone Solvate Form I ofCompound 1.

FIG. 39 shows DSC data for the crystalline Acetone Solvate Form I ofCompound 1.

FIG. 40 shows TGA data for the crystalline Acetone Solvate Form I ofCompound 1.

FIG. 41 shows XRPD data for the crystalline Acetone Solvate Form II ofCompound 1.

FIG. 42 shows DSC data for the crystalline Acetone Solvate Form II ofCompound 1.

FIG. 43 shows TGA data for the crystalline Acetone Solvate Form II ofCompound 1.

FIG. 44 shows XRPD data for the crystalline p-Dioxane Solvate Form I ofCompound 1.

FIG. 45 shows DSC data for the crystalline p-Dioxane Solvate Form I ofCompound 1.

FIG. 46 shows TGA data for the crystalline p-Dioxane Solvate Form I ofCompound 1.

FIG. 47 shows XRPD data for the crystalline MeOH Solvate Form I ofCompound 1.

FIG. 48 shows DSC data for the crystalline MeOH Solvate Form I ofCompound 1.

FIG. 49 shows TGA data for the crystalline MeOH Solvate Form I ofCompound 1.

FIG. 50 shows XRPD data for the crystalline IPA Solvate Form I ofCompound 1.

FIG. 51 shows DSC data for the crystalline IPA Solvate Form I ofCompound 1.

FIG. 52 shows TGA data for the crystalline IPA Solvate Form I ofCompound 1.

FIG. 53 shows XRPD data for the crystalline EtOH Solvate Form I ofCompound 1.

FIG. 54 shows DSC data for the crystalline EtOH Solvate Form I ofCompound 1.

FIG. 55 shows TGA data for the crystalline EtOH Solvate Form I ofCompound 1.

FIG. 56 is the overlay XRPD data for the isostructural solvate forms ofCompound 1 (Top to bottom—THF, MeCN, MEK, DCM, acetone, MeOH, IPA,EtOH).

DETAILED DESCRIPTION Definitions

The term “Compound 1” means6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one.

Certain of the compounds disclosed herein may exist as atropisomers,which are conformational stereoisomers that occur when rotation about asingle bond in the molecule is prevented, or greatly slowed, as a resultof steric interactions with other parts of the molecule. The compoundsdisclosed herein include all atropisomers, both as pure individualatropisomer preparations, enriched preparations of each, or anon-specific mixture of each. Where the rotational barrier about thesingle bond is high enough, and interconversion between conformations isslow enough, separation and isolation of the isomeric species may bepermitted. For example, Compound 1 is

atropisomer M and may exhibit restricted rotation. The M-atropisomer ofCompound 1 is also known as AMG 510. Canon, J., et al., Nature575(7781):217-223 (2019), FIG. 1 a.

Alternatively, Compound 1 has the following atropisomer P and mayexhibit restricted rotation.

Abbreviations: The following abbreviations may be used herein:

AcOH acetic acid aq or aq. aqueous DCM dichloromethane DME1,2-dimethoxyethane DMF N,N-dimethylformamide DMSO dimethyl sulfoxide eqor eq. or equiv. equivalent ESI or ES electrospray ionization Et ethylEt₂O diethyl ether EtOAc ethyl acetate EtOH ethanol g gram(s) h hour(s)HPLC high pressure liquid chromatography IPA Isopropyl alcohol iPrisopropyl iPr₂NEt or DIPEA N-ethyl diisopropylamine (Hünig's base) LCMS, LCMS, liquid chromatography mass spectroscopy LC-MS or LC/MS LGleaving group (e.g., halogen, mesylate, triflate) m/z mass divided bycharge Me methyl MeCN acetonitrile MeOH Methanol MEK Methyl ethyl ketoneMet metal species for cross-coupling (e.g., MgX, ZnX, SnR₃, SiR₃,B(OR)₂) mg milligrams min minutes mL milliliters MS mass spectra NaHMDSsodium hexamethyldisilazide NBS N-bromosuccinimide n-BuLi n-butyllithiumNCS N-chlorosuccinimide NMR nuclear magnetic resonance Pd₂(dba)₃tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl₂ · DCM,[1,1′-bis(diphenylphosphino)ferrocene] Pd(dppf)Cl₂dichloropalladium(II), complex with dichloromethane Pd(PPh₃)₄tetrakis(triphenylphosphine)palladium(0) Ph phenyl ppm parts per millionPR or PG or protecting group Prot. group rbf round-bottomed flaskRP-HPLC reverse phase high pressure liquid chromatography RT or rt orr.t. room temperature sat. or satd. saturated SFC supercritical fluidchromatography SPhos Pd G3 or(2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl) SPhos G3[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate SSNMR Solidstate nuclear magnetic resonance TBAF tetra-n-butylammonium fluorideTBTU N,N,N′,N′-tetramethy1-O-(benzotriazol-1-yl)uroniumtetrafluoroborate t-BuOH tert-butanol TEA or Et₃N trimethylamine TFAtrifluoroacetic acid THF tetrahydrofuran UV ultraviolet

The use of the terms “a,” “an,” ˜ “the,” ˜ and similar referents in thecontext of the disclosure (especially in the context of the claims) areto be construed to cover both the singular and the plural, unlessotherwise indicated. Recitation of ranges of values herein merely areintended to serve as a shorthand method of referring individually toeach separate value falling within the range, unless otherwise indicatedherein, and each separate value is incorporated into the specificationas if it were individually recited herein. The use of any and allexamples, or exemplary language (e.g., “such as”) provided herein, isintended to better illustrate the invention and is not a limitation onthe scope of the invention unless otherwise claimed. No language in thespecification should be construed as indicating any non-claimed elementas essential to the practice of the invention.

The term “anhydrous form of Compound 1” means a form of Compound 1substantially or completely free from water and particularly water ofcrystallization. Those skilled in the art appreciate that the exactnumber of water molecules may vary slightly at any time with variabletemperature, pressure, and other environmental influences. All slightvariations of the number of the associated water molecules arecontemplated to be within the scope of the present disclosure.

The term “co-crystal” means a crystalline material comprising two ormore compounds at ambient temperature (20° C. to 25° C., preferably 20°C.), of which at least two are held together by weak interaction,wherein at least one of the compounds is a co-crystal former and theother is Compound 1. Weak interaction is being defined as an interactionwhich is neither ionic nor covalent and includes for example: hydrogenbonds, van der Waals forces, and π-π interactions. The term “co-crystal”includes solvate forms.

The term “amorphous form” or “amorphous” means a material that lackslong range order and as such does not show distinct X-ray diffractionpeaks, i.e. a Bragg diffraction peak. The XRPD pattern of an amorphousmaterial is characterized by one or more amorphous halos.

The term “amorphous halo” is an approximately bell-shaped maximum in theX-ray powder pattern of an amorphous substance.

The term “excipient” means any pharmaceutically acceptable additive,carrier, diluent, adjuvant, or other ingredient, other than the activepharmaceutical ingredient (API), which is typically included forformulation and/or administration to a patient.

The term “a disease mediated by KRAS G12C inhibition” means (i) cancersand (ii) solid tumors. KRAS is the most frequently mutated oncogene incancer and encodes a key signalling protein in tumors. Canon, J., etal., Nature 575(7781):217-223 (2019), abstract. The KRAS(G12C) mutanthas a cysteine residue that has been exploited to design covalentinhibitors that have promising preclinical activity. Id. A series ofinhibitors was optimized, using novel binding interactions to markedlyenhance their potency and selectivity. Id. The efforts have led to thediscovery of AMG 510. Id. In preclinical analyses, treatment with AMG510 led to the regression of KRAS^(G12C) tumors and improved theanti-tumor efficacy of chemotherapy and targeted agents. Id. Inimmune-competent mice, treatment with AMG 510 resulted in apro-inflammatory tumor microenvironment and produced durable cures aloneas well as in combination with immune-checkpoint inhibitors. Id. Curedmice rejected the growth of isogenic KRAS^(G12D) tumors, which suggestsadaptive immunity against shared antigens. Id. Furthermore, in clinicaltrials, AMG 510 demonstrated anti-tumor activity in the first dosingcohorts and represents a potentially transformative therapy for patientsfor whom effective treatments are lacking. Id.

The term “cancer” means a hyperproliferative disorder in a mammal, suchas a human, with a KRAS, HRAS or NRAS G12C mutation, which can betreated by, for example, by administering to said mammal atherapeutically effective amount of Compound 1 as disclosed herein. Insome embodiments, the cancer is, for example, acute myeloid leukemia,cancer in adolescents, adrenocortical carcinoma childhood, AIDS-relatedcancers (e.g. Lymphoma and Kaposi's Sarcoma), anal cancer, appendixcancer, astrocytomas, atypical teratoid, basal cell carcinoma, bile ductcancer, bladder cancer, bone cancer, brain stem glioma, brain tumor,breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumor,atypical teratoid, embryonal tumors, germ cell tumor, primary lymphoma,cervical cancer, childhood cancers, chordoma, cardiac tumors, chroniclymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronicmyeloproliferative disorders, colon cancer, colorectal cancer,craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductalcarcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrialcancer, ependymoma, esophageal cancer, esthesioneuroblastoma, ewingsarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eyecancer, fibrous histiocytoma of bone, gall bladder cancer, gastriccancer, gastrointestinal carcinoid tumor, gastrointestinal stromaltumors (GIST), germ cell tumor, gestational trophoblastic tumor, hairycell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkinlymphoma, hypopharyngeal cancer, intraocular melanoma, islet celltumors, pancreatic neuroendocrine tumors, kidney cancer, laryngealcancer, lip and oral cavity cancer, liver cancer, lobular carcinoma insitu (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer withoccult primary, midline tract carcinoma, mouth cancer, multipleendocrine neoplasia syndromes, multiple myeloma/plasma cell neoplasm,mycosis fungoides, myelodysplastic syndromes,myelodysplastic/myeloproliferative neoplasms, multiple myeloma, merkelcell carcinoma, malignant mesothelioma, malignant fibrous histiocytomaof bone and osteosarcoma, nasal cavity and paranasal sinus cancer,nasopharyngeal cancer, neuroblastoma, non-hodgkin lymphoma, non-smallcell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer,oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis,paraganglioma, paranasal sinus and nasal cavity cancer, parathyroidcancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma,primary central nervous system (CNS) lymphoma, prostate cancer, rectalcancer, transitional cell cancer, retinoblastoma, rhabdomyosarcoma,salivary gland cancer, skin cancer, stomach (gastric) cancer, small celllung cancer, small intestine cancer, soft tissue sarcoma, T-Celllymphoma, testicular cancer, throat cancer, thymoma and thymiccarcinoma, thyroid cancer, transitional cell cancer of the renal pelvisand ureter, trophoblastic tumor, unusual cancers of childhood, urachalcancer, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer,or viral-induced cancer. In some embodiments, said method relates to thetreatment of a non-cancerous hyperproliferative disorder such as benignhyperplasia of the skin (e. g., psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)).

The term “patient” means animals, such as dogs, cats, cows, horses,sheep and humans. Particular patients are mammals. The term patientincludes males and females.

The term “therapeutically effective amount” means an amount of acompound that ameliorates, attenuates or eliminates one or more symptomof a particular disease or condition, or prevents or delays the onset ofone of more symptoms of a particular disease or condition.

The term “pharmaceutically acceptable” means that the referencedsubstance, such as a compound of the present disclosure or a formulationcontaining a compound of the present disclosure, or a particularexcipient, are suitable for administration to a patient.

As used herein and unless otherwise indicated, the terms “polymorph” and“polymorphic form” refer to solid crystalline forms of a compound orcomplex. Different polymorphs of the same compound can exhibit differentphysical, chemical and/or spectroscopic properties. Different physicalproperties include, but are not limited to stability (e.g., to heat orlight), compressibility and density (important in formulation andproduct manufacturing), and dissolution rates (which can affectbioavailability). Differences in stability can result from changes inchemical reactivity (e.g., differential oxidation, such that a dosageform discolors more rapidly when comprised of one polymorph than whencomprised of another polymorph) or mechanical characteristics (e.g.,tablets crumble on storage as a kinetically favored polymorph convertsto thermodynamically more stable polymorph) or both (e.g., tablets ofone polymorph are more susceptible to breakdown at high humidity).Different physical properties of polymorphs can affect their processing.For example, one polymorph might be more likely to form solvates ormight be more difficult to filter or wash free of impurities thananother due to, for example, the shape or size distribution of particlesof it.

Polymorphs of a molecule can be obtained by a number of methods known inthe art. Such methods include, but are not limited to, meltrecrystallization, melt cooling, solvent recrystallization, desolvation,rapid evaporation, rapid cooling, slow cooling, vapor diffusion andsublimation. Polymorphs can be detected, identified, classified andcharacterized using well-known techniques such as, but not limited to,differential scanning calorimetry (DSC), thermogravimetry (TGA), X-raypowder diffractometry (XRPD), single crystal X-ray diffractometry,vibrational spectroscopy, solution calorimetry, solid state nuclearmagnetic resonance (NMR), infrared (IR) spectroscopy, Ramanspectroscopy, hot stage optical microscopy, scanning electron microscopy(SEM), electron crystallography and quantitative analysis, particle sizeanalysis (PSA), surface area analysis, solubility, and rate ofdissolution.

As used herein to refer to the spectra or data presented in graphicalform (e.g., XRPD, IR, Raman and NMR spectra), and unless otherwiseindicated, the term “peak” refers to a peak or other special featurethat one skilled in the art would recognize as not attributable tobackground noise.

As used herein and unless otherwise indicated, the term “substantiallypure” when used to describe a polymorph of a compound means a solid formof the compound that comprises that polymorph and is substantially freeof other polymorphs of the compound. A representative substantially purepolymorph comprises greater than about 80% by weight of one polymorphicform of the compound and less than about 20% by weight of otherpolymorphic forms of the compound, more preferably greater than about90% by weight of one polymorphic form of the compound and less thanabout 10% by weight of the other polymorphic forms of the compound, evenmore preferably greater than about 95% by weight of one polymorphic formof the compound and less than about 5% by weight of the otherpolymorphic forms of the compound, and most preferably greater thanabout 97% by weight of one polymorphic forms of the compound and lessthan about 3% by weight of the other polymorphic forms of the compound.

The terms “treating”, “treat” or “treatment” and the like includepreventative (e.g., prophylactic) and palliative treatment.

The term “variable hydrate” means a hydrate of Compound 1 having atleast about one, two, three, or four associated water molecules. In someembodiments, the hydrates of the present disclosure include from atleast one to ten associated molecules of water. Those skilled in the artappreciate that the exact number of the associated water molecules mayvary slightly at any time with variable temperature, pressure, and otherenvironmental influence. All slight variations of the number of theassociated water molecules are contemplated to be within the scope ofthe present disclosure.

In some embodiments, the methods for treatment are directed to treatinglung cancers, the methods comprise administering an effective amount ofany of the above described compounds (or a pharmaceutical compositioncomprising the same) to a subject in need thereof. In certainembodiments the lung cancer is a non-small cell lung carcinoma (NSCLC),for example adenocarcinoma, squamous-cell lung carcinoma or large-celllung carcinoma. In some embodiments, the lung cancer is a small celllung carcinoma. Other lung cancers treatable with the disclosedcompounds include, but are not limited to, glandular tumors, carcinoidtumors and undifferentiated carcinomas. In one embodiment the NSCLC islocally advanced or metastatic.

The compounds of the present disclosure are administered to a patient ina therapeutically effective amount. The compounds can be administeredalone or as part of a pharmaceutically acceptable composition orformulation. In addition, the compounds or compositions can beadministered all at once, as for example, by a bolus injection, multipletimes, such as by a series of tablets, or delivered substantiallyuniformly over a period of time, as for example, using transdermaldelivery. It is also noted that the dose of the compound can be variedover time.

In addition, the compounds of the present disclosure can be administeredalone, in combination with other compounds of the present disclosure, orwith other pharmaceutically active compounds. The other pharmaceuticallyactive compounds can be intended to treat the same disease or conditionas the compounds of the present disclosure or a different disease orcondition. If the patient is to receive or is receiving multiplepharmaceutically active compounds, the compounds can be administeredsimultaneously, or sequentially. For example, in the case of tablets,the active compounds may be found in one tablet or in separate tablets,which can be administered at once or sequentially in any order. Inaddition, it should be recognized that the compositions may be differentforms. For example, one or more compound may be delivered via a tablet,while another is administered via injection or orally as a syrup. Allcombinations, delivery methods and administration sequences arecontemplated.

It is also noted that the solid state forms of the present disclosurecan be administered together. For example, substantially purecrystalline anhydrous form I of Compound 1 can be administered to apatient. Alternatively, about 90% by weight of crystalline anhydrousform I of Compound 1 can be administered with the remaining Compound 1present in other forms, such as the amorphous form of Compound I. Inanother embodiment, 80% by weight of crystalline anhydrous form I ofCompound 1 can be administered with the remaining Compound 1 present inother forms, such as the amorphous form. All combinations arecontemplated. In one embodiment of the disclosure, Compound 1 isadministered to a patient in one substantially pure form. Those skilledin the art will appreciate the possible variations.

The compounds of the present disclosure may be used in the manufactureof a medicament for the treatment of a disease mediated by KRAS G12Cinhibition, such as cancer, including but not limited to colorectalcancer, pancreatic cancer and lung cancer, such as non-small cell lungcancer (NSCLC).

In still a further aspect, the disclosure relates to the use of a salt,a crystalline form, an amorphous form, or co-crystal of Compound 1 forthe preparation of a medicament useful for treating cancer, such ascolorectal cancer, pancreatic cancer and lung cancer, such as non-smallcell lung cancer (NSCLC).

Since one aspect of the present disclosure contemplates the treatment ofthe disease/conditions with a combination of pharmaceutically activecompounds that may be administered separately, the disclosure furtherrelates to combining separate pharmaceutical compositions in kit form.The kit comprises two separate pharmaceutical compositions: a compoundof the present disclosure, and a second pharmaceutical compound. The kitcomprises a container for containing the separate compositions such as adivided bottle or a divided foil packet. Additional examples ofcontainers include syringes, boxes and bags. Typically, the kitcomprises directions for the use of the separate components. The kitform is particularly advantageous when the separate components arepreferably administered in different dosage forms (e.g., oral andparenteral), are administered at different dosage intervals, or whentitration of the individual components of the combination is desired bythe prescribing physician or veterinarian.

An example of such a kit is a so-called blister pack. Blister packs arewell known in the packaging industry and are being widely used for thepackaging of pharmaceutical unit dosage forms (tablets, capsules, andthe like). Blister packs generally consist of a sheet of relativelystiff material covered with a foil of a preferably transparent plasticmaterial. During the packaging process recesses are formed in theplastic foil. The recesses have the size and shape of the tablets orcapsules to be packed. Next, the tablets or capsules are placed in therecesses and the sheet of relatively stiff material is sealed againstthe plastic foil at the face of the foil which is opposite from thedirection in which the recesses were formed. As a result, the tablets orcapsules are sealed in the recesses between the plastic foil and thesheet. Preferably the strength of the sheet is such that the tablets orcapsules can be removed from the blister pack by manually applyingpressure on the recesses whereby an opening is formed in the sheet atthe place of the recess. The tablet or capsule can then be removed viasaid opening.

It may be desirable to provide a memory aid on the kit, e.g., in theform of numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen which the tablets or capsules sospecified should be ingested. Another example of such a memory aid is acalendar printed on the card, e.g., as follows “First Week, Monday,Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . “etc.Other variations of memory aids will be readily apparent. A “daily dose”can be a single tablet or capsule or several pills or capsules to betaken on a given day. Also, a daily dose of a compound of the presentdisclosure can consist of one tablet or capsule, while a daily dose ofthe second compound can consist of several tablets or capsules and viceversa. The memory aid should reflect this and aid in correctadministration of the active agents.

In another specific embodiment of the disclosure, a dispenser designedto dispense the daily doses one at a time in the order of their intendeduse is provided. Preferably, the dispenser is equipped with amemory-aid, so as to further facilitate compliance with the regimen. Anexample of such a memory-aid is a mechanical counter which indicates thenumber of daily doses that has been dispensed. Another example of such amemory-aid is a battery-powered micro-chip memory coupled with a liquidcrystal readout, or audible reminder signal which, for example, readsout the date that the last daily dose has been taken and/or reminds onewhen the next dose is to be taken.

The compounds of the present disclosure and other pharmaceuticallyactive compounds, if desired, can be administered to a patient eitherorally, rectally, parenterally, (for example, intravenously,intramuscularly, or subcutaneously) intracisternally, intravaginally,intraperitoneally, intravesically, locally (for example, powders,ointments or drops), or as a buccal or nasal spray. All methods that areused by those skilled in the art to administer a pharmaceutically activeagent are contemplated. In one embodiment, the compounds of the presentdisclosure and other pharmaceutically active compounds, if desired, canbe administered to a patient orally.

Compositions suitable for parenteral injection may comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions, or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents,solvents, or vehicles include water, ethanol, polyols (propylene glycol,polyethylene glycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil) and injectable organic esters such asethyl oleate. Proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preserving,wetting, emulsifying, and dispersing agents. Microorganism contaminationcan be prevented by adding various antibacterial and antifungal agents,for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.It may also be desirable to include isotonic agents, for example,sugars, sodium chloride, and the like. Prolonged absorption ofinjectable pharmaceutical compositions can be brought about by the useof agents delaying absorption, for example, aluminum monostearate andgelatin.

Solid dosage forms for oral administration include capsules, tablets,powders, and granules. In such solid dosage forms, the active compoundis admixed with at least one inert customary excipient (or carrier) suchas sodium citrate or dicalcium phosphate or (a) fillers or extenders, asfor example, starches, lactose, sucrose, mannitol, and silicic acid; (b)binders, as for example, carboxymethylcellulose, alginates, gelatin,polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, as forexample, glycerol; (d) disintegrating agents, as for example, agar-agar,calcium carbonate, potato or tapioca starch, alginic acid, certaincomplex silicates, and sodium carbonate; (a) solution retarders, as forexample, paraffin; (f) absorption accelerators, as for example,quaternary ammonium compounds; (g) wetting agents, as for example, cetylalcohol and glycerol monostearate; (h) adsorbents, as for example,kaolin and bentonite; and (i) lubricants, as for example, talc, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate, or mixtures thereof. In the case of capsules, and tablets, thedosage forms may also comprise buffering agents. In one embodiment thedosage form contemplated in this disclosure is a solid dosage for, suchas a tablet for oral administration.

Solid compositions of a similar type may also be used as fillers in hardfilled gelatin capsules using such excipients as lactose, as well ashigh molecular weight polyethylene glycols, and the like.

Solid dosage forms such as tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells, such as entericcoatings and others well known in the art. They may also containopacifying agents, and can also be of such composition that they releasethe active compound or compounds in a certain part of the intestinaltract in a delayed manner. Examples of embedding compositions that canbe used are polymeric substances and waxes. The active compounds canalso be in micro-encapsulated form, if appropriate, with one or more ofthe above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs, forexample in a soft filled gelatin capsules. In addition to the activecompounds, the liquid dosage form may contain inert diluents commonlyused in the art, such as water or other solvents, solubilizing agentsand emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils, in particular,cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, andsesame seed oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan, or mixtures of thesesubstances, and the like.

Besides such inert diluents, the composition can also include adjuvants,such as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents. Suspensions, in addition to the activecompound, may contain suspending agents, as for example, ethoxylatedisostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters,microcrystalline cellulose, aluminum metahydroxide, bentonite,agar-agar, and tragacanth, or mixtures of these substances, and thelike.

Compositions for rectal administration are preferable suppositories,which can be prepared by mixing the compounds of the present disclosurewith suitable non-irritating excipients or carriers such as cocoabutter, polyethylene glycol or a suppository wax, which are solid atordinary room temperature, but liquid at body temperature, andtherefore, melt in the rectum or vaginal cavity and release the activecomponent.

Dosage forms for topical administration of a compound of the presentdisclosure include ointments, powders, sprays and inhalants. The activecompound or fit compounds are admixed under sterile condition with aphysiologically acceptable carrier, and any preservatives, buffers, orpropellants that may be required. Ophthalmic formulations, eyeointments, powders, and solutions are also contemplated as being withinthe scope of this disclosure.

The compounds of the present disclosure can be administered to a patientat dosage levels in the range of about 0.1 to about 2000 mg per day,preferably from 5 mg to 1000 mg per day. For a normal adult human havinga body weight of about 70 kg, a dosage in the range of about 0.001 mgper kilogram body weight to about 20 mg per kilogram body weight istypically sufficient. The specific dosage and dosage range that can beused depends on a number of factors, including the requirements of thepatient, the severity of the condition or disease being treated, and thepharmacological activity of the compound being administered. Thedetermination of dosage ranges and optimal dosages for a particularpatient is within the ordinary skill in the art. In one embodiment thetotal daily dose administered to a patient is 180 mg, 360 mg, 720 mg, or960 mg. The total daily dose can be administered orally with multipletablets containing, e.g., 120 mg of Compound 1 (e.g., the total dailydose of 960 mg is administered with 8 tablets of 120 mg of Compound 1each). In one embodiment the total daily dose administered to a patientis 960 mg of Compound 1. In one embodiment the total daily dose of 960mg of Compound 1 is administered with 8 tablets comprising 120 mg ofCompound 1.

Unless specifically stated otherwise, the compounds of the presentdisclosure may exist in unsolvated as well as solvated forms withpharmaceutically acceptable solvents such as water (hydrate), ethanol,and the like. The present disclosure contemplates and encompasses boththe solvated and unsolvated forms.

It is also possible that compounds of the present disclosure may existin different tautomeric forms. All tautomers of compounds of the presentdisclosure are contemplated. For example, all keto-enol forms of thecompounds are included in this disclosure.

Those skilled in the art will recognize that the compound names andstructures contained herein may be based on a particular tautomer of acompound. While the name or structure for only a particular tautomer maybe used, it is intended that all tautomers are encompassed by thepresent disclosure, unless stated otherwise.

Those skilled in the art will understand that the anhydrous free forms,hydrates, salts and co-crystals of Compound 1 may exist in one or moreionization states. which typically exists as zwitterions. While the nameor structure for only a particular ionization state may be used, it isintended that all ionization states are encompassed by the presentdisclosure, unless stated otherwise.

It is also intended that the present disclosure encompasses compoundsthat are synthesized in vitro using laboratory techniques, such as thosewell known to synthetic chemists; or synthesized using in vivotechniques, such as through metabolism, fermentation, digestion, and thelike. It is also contemplated that the compounds of the presentdisclosure may be synthesized using a combination of in vitro and invivo techniques.

The present disclosure also includes isotopically-labelled compounds,which are identical to those recited herein, but for the fact that oneor more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁶O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl.

Compounds of the present disclosure that contain the aforementionedisotopes and/or other isotopes of other atoms are within the scope ofthis disclosure. Certain isotopically-labelled compounds of the presentdisclosure, for example those into which radioactive isotopes such as ³Hand ¹⁴C are incorporated, are useful in drug and/or substrate tissuedistribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C,isotopes are particularly preferred for their ease of preparation anddetection. Further, substitution with heavier isotopes such asdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances. Isotopically labelled compounds of this disclosurecan generally be prepared by substituting a readily availableisotopically labelled reagent for a non-isotopically labelled reagent.

All patents and other publications recited herein are herebyincorporated by reference.

The examples and embodiments presented below are illustrative of theinvention disclosed herein and are not intended to limit the scope ofthe claims in any manner.

EMBODIMENTS

1. In one embodiment, the present invent provides a crystallineanhydrous form I of6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one(Compound 1).

2. In another embodiment, the present disclosure provides thecrystalline anhydrous form I of embodiment 1, wherein the anhydrous formI is the M atropisomer.

3. In another embodiment, the present disclosure provides thecrystalline anhydrous form I of embodiment 1, wherein the crystallineanhydrous form I is characterized by the powder X-ray diffractionpattern substantially as shown in FIG. 5.

4. In another embodiment, the present disclosure provides thecrystalline anhydrous form I of embodiment 1, wherein said crystallineanhydrous form I is characterized by at least three peaks, at least fivepeaks, or at least seven peaks selected from a powder X-ray diffractionpattern comprising peaks at diffraction angle 2 theta degrees atapproximately 8.8, 9.0, 10.8, 12.0, 12.6, 12.8, 13.6, 14.2, 15.0, 15.4,18.0, 18.6, 18.7, 19.0, 19.9, 20.0, 22.9, and 25.0.

5. In another embodiment, the present disclosure provides thecrystalline anhydrous form I of embodiment 1, wherein said crystallineanhydrous form I is characterized by a powder X-ray diffraction patterncomprising peaks at diffraction angle 2 theta degrees at approximately9.0, 12.0, 12.6 and 19.0.

6. In another embodiment, the present disclosure provides thecrystalline anhydrous form I of embodiment 1 having a differentialscanning calorimetry thermogram comprising an endotherm with an onset ofabout 293° C.

7. In another embodiment, the present disclosure provides thecrystalline anhydrous form of embodiment 1 having a thermogravimetricanalysis thermogram comprising a weight loss of about 0.2% when heatedfrom about 25° C. to about 275° C.

8. In another embodiment, the present disclosure provides thecrystalline anhydrous form of embodiment 1, wherein said crystallineanhydrous form I is characterized by ¹³C solid state NMR as depicted inFIG. 8.

9. In another embodiment, the present disclosure provides thecrystalline anhydrous form of embodiment 1, wherein said crystallineanhydrous form I is characterized by ¹³C solid state NMR, comprisingpeaks at approximately 12, 13, 16, 21, 23, 31, 33, 38, 42, 44, 47, 50,54, 107, 110, 111, 123, 124, 127, 128, 132, 145, 146, 150, 154, 156,158, 160, 162, 166, 167.7 and 168 ppm.

10. In another embodiment, the present disclosure provides thecrystalline anhydrous form of embodiment 1, wherein said crystallineanhydrous form I is characterized by ¹⁹F solid state NMR as depicted inFIG. 9.

11. In another embodiment, the present disclosure provides thecrystalline anhydrous form of embodiment 1, wherein said crystallineanhydrous form I is characterized by ¹⁹F solid state NMR, comprisingpeaks at approximately −49, −60, −79, −90, −109, −120, −138, −150, −168and −179 ppm.

12. In another embodiment, the present disclosure provides thecrystalline anhydrous form of embodiment 1 which is substantially pure.

13. In another embodiment, the present disclosure provides apharmaceutical composition comprising the crystalline anhydrous form Iof embodiment 1, and a pharmaceutically acceptable excipient.

14. In another embodiment, the present disclosure provides thepharmaceutical composition comprising the crystalline anhydrous form Ias in any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or13, or a mixture thereof, and a pharmaceutically acceptable excipient.

15. In another embodiment, the present disclosure provides thepharmaceutical composition of embodiment 14, wherein the composition isa single dose.

16. In another embodiment, the present disclosure provides a compositioncomprising an amorphous form of6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-oneand the crystalline anhydrous form I of embodiment 1.

17. In another embodiment, the present disclosure provides a method forpreparing the crystalline anhydrous form I of embodiment 1, the methodcomprising: combining form II of Compound 1 and a suitable solvent, andremoving the solvent to form a crystalline anhydrous form I of Compound1.

18. In another embodiment, the present disclosure provides the method ofembodiment 17, wherein the suitable solvent is water.

19. In another embodiment, the present disclosure provides a method oftreating a disease mediated by KRAS G12C inhibition, the methodcomprising administering to a patient in need thereof a pharmaceuticallyeffective amount of a pharmaceutical composition comprising thecrystalline anhydrous form I of embodiment 1.

20. In another embodiment, the present disclosure provides a method oftreating a disease mediated by KRAS G12C inhibition, the methodcomprising administering to a patient in need thereof a pharmaceuticallyeffective amount of a pharmaceutical composition of embodiment 14.

21. In another embodiment, the present disclosure provides the method ofembodiment 19, wherein said disease mediated by G12C inhibition iscancer.

22. In another embodiment, the present disclosure provides the method ofembodiment 21, wherein the cancer is lung cancer, pancreatic cancer orcolorectal cancer.

23. In another embodiment, the present disclosure provides the method ofembodiment 22, wherein the cancer is lung cancer.

24. In another embodiment, the present disclosure provides the method ofembodiment 23, wherein the lung cancer is non-small cell lung cancer.

25. In another embodiment, the present disclosure provides an amorphousform of6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one.

26. In another embodiment, the present disclosure provides the amorphousform of6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-oneof embodiment 25, characterized by the powder X-ray diffraction patternsubstantially as shown in FIG. 1.

27. In another embodiment, the present disclosure provides the amorphousform of embodiment 25, wherein the form is the M atropisomer.

28. In another embodiment, the present disclosure provides the amorphousform of embodiment 25 having a differential scanning calorimetrythermogram comprising an endotherm with an onset of about 144° C.

29. In another embodiment, the present disclosure provides the amorphousform of embodiment 25 having a thermogravimetric analysis thermogramcomprising a weight loss of about 1.5% when heated from about 25° C. toabout 275° C.

30. In another embodiment, the present disclosure provides the amorphousform of embodiment 25, wherein said form is characterized by ¹⁹F solidstate NMR as depicted in FIG. 4.

31. In another embodiment, the present disclosure provides the amorphousform of embodiment 25, wherein said form is characterized by ¹⁹F solidstate NMR, comprising peaks at approximately −86, −96, −116, −127, −146and −156 ppm.

32. In another embodiment, the present disclosure provides the amorphousform of embodiment 25 which is substantially pure.

33. In another embodiment, the present disclosure provides apharmaceutical composition comprising the amorphous form of embodiment25, and a pharmaceutically acceptable excipient.

34. In another embodiment, the present disclosure provides apharmaceutical composition comprising the amorphous form as in any oneof embodiments 25, 26, 27, 28, 29, 30, 31, 32 or 33, or a mixturethereof, and a pharmaceutically acceptable excipient.

35. In another embodiment, the present disclosure provides apharmaceutical composition of embodiment 34, wherein the composition isa single dose.

36. In another embodiment, the present disclosure provides a method forpreparing the amorphous form of embodiment 35, the method comprisingdissolving Compound 1 and a suitable solvent to form an amorphous formof Compound 1.

37. In another embodiment, the present disclosure provides the method ofembodiment 36 wherein the suitable solvent is methanol.

38. In another embodiment, the present disclosure provides a method oftreating a disease mediated by KRAS G12C inhibition, the methodcomprising administering to a patient in need thereof a pharmaceuticallyeffective amount of a pharmaceutical composition comprising theamorphous form of embodiment 25.

39. In another embodiment, the present disclosure provides the method ofembodiment 38, wherein said disease mediated by G12C inhibition iscancer.

40. In another embodiment, the present disclosure provides the method ofembodiment 39, wherein the cancer is lung cancer, pancreatic cancer orcolorectal cancer.

41. In another embodiment, the present disclosure provides the method ofembodiment 40, wherein the cancer is lung cancer.

42. In another embodiment, the present disclosure provides the method ofembodiment 41, wherein the lung cancer is non-small cell lung cancer.

43. In another embodiment, the present disclosure provides a crystallineanhydrous form II of6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one(Compound 1).

44. In another embodiment, the present disclosure provides thecrystalline anhydrous form II of embodiment 43, wherein the anhydrousform II is the M atropisomer.

45. In another embodiment, the present disclosure provides thecrystalline anhydrous form II of embodiment 43, characterized by thepowder X-ray diffraction pattern substantially as shown in FIG. 10.

46. In another embodiment, the present disclosure provides thecrystalline anhydrous form II of Compound 1 of embodiment 43, whereinsaid form is characterized by at least three peaks, at least five peaks,or at least seven peaks selected from a powder X-ray diffraction patterncomprising peaks at diffraction angle 2 theta degrees at approximately7.3, 9.8, 10.1, 10.4, 11.3, 11.5, 11.9, 13.3, 14.3, 14.7, 17.2, and18.4.

47. In another embodiment, the present disclosure provides thecrystalline anhydrous form II of Compound II of embodiment 43, whereinsaid form is characterized by a powder X-ray diffraction patterncomprising peaks at diffraction angle 2 theta degrees at approximately7.3, 9.8, 10.1, 11.3, 13.3 and 17.2.

48. In another embodiment, the present disclosure provides thecrystalline anhydrous form II of embodiment 43 having a differentialscanning calorimetry thermogram comprising an endotherm with an onset ofabout 193° C.

49. In another embodiment, the present disclosure provides thecrystalline anhydrous form II of embodiment 43 having athermogravimetric analysis thermogram comprising a weight loss of about1% to about 1.8% when heated from about 25° C. to about 250° C.

50. In another embodiment, the present disclosure provides thecrystalline anhydrous form II of embodiment 43, wherein said form ischaracterized by ¹³C solid state NMR as depicted in FIG. 13.

51. In another embodiment, the present disclosure provides thecrystalline anhydrous form II of embodiment 43, wherein said form ischaracterized by ¹³C solid state NMR, comprising peaks at approximately16, 18, 19, 20, 23, 25, 31, 32, 38, 40, 43, 46, 51, 57, 105, 107, 110,117, 120, 123, 124, 125, 128, 132, 149, 152, 155, 158, 159, 163 and 166ppm.

52. In another embodiment, the present disclosure provides thecrystalline anhydrous form II of embodiment 43, wherein said form ischaracterized by ¹⁹F solid state NMR as depicted in FIG. 14.

53. In another embodiment, the present disclosure provides thecrystalline anhydrous form II of embodiment 43, wherein said form ischaracterized by ¹⁹F solid state NMR, comprising peaks at approximately−59, −62, −89, −92, −119, −122, −148, −151, −179 and −181 ppm.

54. In another embodiment, the present disclosure provides thecrystalline anhydrous form II of embodiment 43 which is substantiallypure.

55. In another embodiment, the present disclosure provides apharmaceutical composition comprising the crystalline anhydrous form IIof embodiment 43, and a pharmaceutically acceptable excipient.

56. In another embodiment, the present disclosure provides apharmaceutical composition comprising the crystalline anhydrous form IIas in any one of embodiments 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53,54 or 55, or a mixture thereof, and a pharmaceutically acceptableexcipient.

57. In another embodiment, the present disclosure provides thepharmaceutical composition of embodiment 56, wherein the composition isa single dose.

58. In another embodiment, the present disclosure provides thecomposition comprising an amorphous form of6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-oneand the crystalline anhydrous form II of embodiment 43.

59. In another embodiment, the present disclosure provides a method forpreparing the crystalline anhydrous form II of embodiment 43, the methodcomprising: combining an amorphous form of Compound 1 and a suitablesolvent to form a crystalline anhydrous form II of Compound 1.

60. In another embodiment, the present disclosure provides the method ofembodiment 59 wherein the suitable solvent is methanol.

61. In another embodiment, the present disclosure provides a method oftreating a disease mediated by KRAS G12C inhibition, the methodcomprising administering to a patient in need thereof a pharmaceuticallyeffective amount of a pharmaceutical composition comprising thecrystalline anhydrous form II of embodiment 43.

62. In another embodiment, the present disclosure provides the method ofembodiment 61, wherein said disease mediated by G12C inhibition iscancer.

63. In another embodiment, the present disclosure provides the method ofembodiment 62, wherein the cancer is lung cancer, pancreatic cancer orcolorectal cancer.

64. In another embodiment, the present disclosure provides the method ofembodiment 63, wherein the cancer is lung cancer.

65. In another embodiment, the present disclosure provides the method ofembodiment 64, wherein the lung cancer is non-small cell lung cancer.

66. In another embodiment, the present disclosure provides a crystallineanhydrous form III of6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one(Compound 1).

67. In another embodiment, the present disclosure provides thecrystalline anhydrous form III of embodiment 66, wherein the anhydrousform III is the M atropisomer.

68. In another embodiment, the present disclosure provides thecrystalline anhydrous form III of embodiment 66, characterized by thepowder X-ray diffraction pattern substantially as shown in FIG. 15.

69. In another embodiment, the present disclosure provides thecrystalline anhydrous form III of Compound 1 of embodiment 66, whereinsaid form is characterized by at least three peaks, at least five peaks,or at least seven peaks selected from a powder X-ray diffraction patterncomprising peaks at diffraction angle 2 theta degrees at approximately6.3, 8.4, 9.5, 10.4, 14.9, 15.4, 15.5, 16.0, and 17.6.

70. In another embodiment, the present disclosure provides thecrystalline anhydrous form III of Compound II of embodiment 66, whereinsaid form is characterized by a powder X-ray diffraction patterncomprising peaks at diffraction angle 2 theta degrees at approximately6.3, 8.4, 9.5, 15.5, and 16.0.

71. In another embodiment, the present disclosure provides thecrystalline anhydrous form III of embodiment 66 having a differentialscanning calorimetry thermogram comprising an endotherm with an onset ofabout 194° C.

72. In another embodiment, the present disclosure provides thecrystalline anhydrous form III of embodiment 66 having athermogravimetric analysis thermogram comprising an approximatenegligible weight loss when heated from about 25° C. to about 250° C.

73. In another embodiment, the present disclosure provides thecrystalline anhydrous form III of embodiment 66 which is substantiallypure.

74. In another embodiment, the present disclosure provides apharmaceutical composition comprising the crystalline anhydrous form IIIof embodiment 66, and a pharmaceutically acceptable excipient.

75. In another embodiment, the present disclosure provides apharmaceutical composition comprising the crystalline anhydrous form IIIas in any one of embodiments 66, 67, 68, 69, 70, 71, 72, 73 or 74, or amixture thereof, and a pharmaceutically acceptable excipient.

76. In another embodiment, the present disclosure provides thepharmaceutical composition of embodiment 75, wherein the composition isa single dose.

77. In another embodiment, the present disclosure provides a compositioncomprising an amorphous form of6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-oneand the crystalline anhydrous form III of embodiment 66.

78. In another embodiment, the present disclosure provides a method forpreparing the crystalline anhydrous form III of embodiment 66, themethod comprising: combining Compound 1 and a suitable solvent to form acrystalline anhydrous form III of Compound 1.

79. In another embodiment, the present disclosure provides the method ofembodiment 78 wherein the suitable solvent is acetone.

80. In another embodiment, the present disclosure provides a method oftreating a disease mediated by KRAS G12C inhibition, the methodcomprising administering to a patient in need thereof a pharmaceuticallyeffective amount of a pharmaceutical composition comprising thecrystalline anhydrous form III of embodiment 66.

81. In another embodiment, the present disclosure provides the method ofembodiment 80, wherein said disease mediated by G12C inhibition iscancer.

82. In another embodiment, the present disclosure provides the method ofembodiment 81, wherein the cancer is lung cancer, pancreatic cancer orcolorectal cancer.

83. In another embodiment, the present disclosure provides the method ofembodiment 82, wherein the cancer is lung cancer.

84. In another embodiment, the present disclosure provides the method ofembodiment 82, wherein the lung cancer is non-small cell lung cancer.

85. In another embodiment, the present disclosure provides a crystallinehydrate form of6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one(Compound 1).

86. In another embodiment, the present disclosure provides thecrystalline hydrate form of embodiment 85, wherein the hydrate form isthe M atropisomer.

87. In another embodiment, the present disclosure provides thecrystalline hydrate form of embodiment 85, characterized by the powderX-ray diffraction pattern substantially as shown in FIG. 18.

88. In another embodiment, the present disclosure provides thecrystalline hydrate form of Compound 1 of embodiment 85, wherein saidform is characterized by at least three peaks, at least five peaks, orat least seven peaks selected from a powder X-ray diffraction patterncomprising peaks at diffraction angle 2 theta degrees at approximately4.0, 4.4, 4.8, 6.9, 8.0, 8.8, 9.6, 11.3, 12.4, 13.0, 13.1, 14.6, 14.9,15.2, 16.2, 16.4, 16.6, 17.3, 17.4, 17.9, and 19.5.

89. In another embodiment, the present disclosure provides thecrystalline hydrate form of Compound I of embodiment 85, wherein saidform is characterized by a powder X-ray diffraction pattern comprisingpeaks at diffraction angle 2 theta degrees at approximately 6.9, 8.0,9.6, 12.4, and 13.1.

90. In another embodiment, the present disclosure provides thecrystalline hydrate form of embodiment 85 having a differential scanningcalorimetry thermogram comprising an endotherm with an onset of about91° C.

91. In another embodiment, the present disclosure provides thecrystalline hydrate form of embodiment 85 having a thermogravimetricanalysis thermogram comprising an approximate 11% weight loss whenheated from about 39° C. to about 160° C.

92. In another embodiment, the present disclosure provides thecrystalline hydrate form of embodiment 85 which is substantially pure.

93. In another embodiment, the present disclosure provides apharmaceutical composition comprising the crystalline hydrate form ofembodiment 85, and a pharmaceutically acceptable excipient.

94. In another embodiment, the present disclosure provides apharmaceutical composition comprising the crystalline hydrate form as inany one of embodiments 85, 86, 87, 88, 89, 90, 91, 92 or 93, or amixture thereof, and a pharmaceutically acceptable excipient.

95. In another embodiment, the present disclosure provides thepharmaceutical composition of embodiment 94, wherein the composition isa single dose.

96. In another embodiment, the present disclosure provides a compositioncomprising an amorphous form of6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-oneand the crystalline hydrate form of embodiment 85.

97. In another embodiment, the present disclosure provides a method forpreparing the crystalline hydrate form of embodiment 85, the methodcomprising: combining Compound 1 and a suitable solvent in the presenceof water to form a crystalline hydrate form of Compound 1.

98. In another embodiment, the present disclosure provides the method ofembodiment 78 wherein the suitable solvent is methanol.

99. In another embodiment, the present disclosure provides a method oftreating a disease mediated by KRAS G12C inhibition, the methodcomprising administering to a patient in need thereof a pharmaceuticallyeffective amount of a pharmaceutical composition comprising thecrystalline hydrate form of embodiment 85.

100. In another embodiment, the present disclosure provides the methodof embodiment 99, wherein said disease mediated by G12C inhibition iscancer.

101. In another embodiment, the present disclosure provides the methodof embodiment 100, wherein the cancer is lung cancer, pancreatic canceror colorectal cancer.

102. In another embodiment, the present disclosure provides the methodof embodiment 101, wherein the cancer is lung cancer.

103. In another embodiment, the present disclosure provides the methodof embodiment 102, wherein the lung cancer is non-small cell lungcancer.

104. In another embodiment, the present disclosure provides acrystalline solvate form of6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one(Compound 1).

105. In another embodiment, the present disclosure provides thecrystalline solvate form of embodiment 104, wherein the solvate form isa THF, MeCN, MEK, EtOAc, DCM, acetone, p-dioxane, methanol, isopropylalcohol, or ethanol solvate form.

106. In another embodiment, the present disclosure provides apharmaceutical composition comprising an amorphous form of6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-oneand at least one crystalline form of6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-oneof any one of embodiments 1, 43, 66, 85 or 104 and a pharmaceuticallyacceptable excipient.

107. In another embodiment, the present disclosure provides thecomposition of embodiment 106, which comprises greater than about 50weight percent crystalline6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one.

108. In another embodiment, the present disclosure provides apharmaceutical composition comprising at least one crystalline form of6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-oneof any one of embodiments 1, 43, 66, 85 or 104 and a pharmaceuticallyacceptable excipient.

Alternative Embodiments

Provided herein as Embodiment 1 is a compound, wherein the compound is acrystalline form of6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one(Compound 1) or an atropisomer thereof.

Provided herein as Embodiment 2 is the compound of Embodiment 1, whereinthe compound is the M atropisomer of Compound 1.

Provided herein as Embodiment 3 is the compound of Embodiment 1 or 2,wherein the compound is a crystalline anhydrous form of Compound 1.

Provided herein as Embodiment 4 is the compound of any one ofEmbodiments 1-3, wherein the compound is characterized by a powder X-raydiffraction pattern comprising peaks at 9.0, 12.0, 12.6, and 19.0±0.2degrees 2 theta as measured by x-ray powder diffraction using an x-raywavelength of 1.54 Å.

Provided herein as Embodiment 5 is the compound of any one ofEmbodiments 1-3, wherein the compound is characterized by a powder X-raydiffraction pattern comprising at least three peaks selected from 8.8,9.0, 10.8, 12.0, 12.6, 12.8, 13.6, 14.2, 15.0, 15.4, 18.0, 18.6, 18.7,19.0, 19.9, 20.0, 22.9, and 25.0±0.2 degrees 2 theta as measured byx-ray powder diffraction using an x-ray wavelength of 1.54 Å.

Provided herein as Embodiment 6 is the compound of any one ofEmbodiments 1-3, wherein the compound is characterized by a powder X-raydiffraction pattern comprising at least five peaks selected from 8.8,9.0, 10.8, 12.0, 12.6, 12.8, 13.6, 14.2, 15.0, 15.4, 18.0, 18.6, 18.7,19.0, 19.9, 20.0, 22.9, and 25.0±0.2 degrees 2 theta as measured byx-ray powder diffraction using an x-ray wavelength of 1.54 Å.

Provided herein as Embodiment 7 is the compound of any one ofEmbodiments 1-3, wherein the compound is characterized by a powder X-raydiffraction pattern comprising at least seven peaks selected from 8.8,9.0, 10.8, 12.0, 12.6, 12.8, 13.6, 14.2, 15.0, 15.4, 18.0, 18.6, 18.7,19.0, 19.9, 20.0, 22.9, and 25.0±0.2 degrees 2 theta as measured byx-ray powder diffraction using an x-ray wavelength of 1.54 Å.

Provided herein as Embodiment 8 is the compound of any one ofEmbodiments 1-3, wherein the compound is characterized by a powder X-raydiffraction pattern comprising peaks at 8.8, 9.0, 10.8, 12.0, 12.6,12.8, 13.6, 14.2, 15.0, 15.4, 18.0, 18.6, 18.7, 19.0, 19.9, 20.0, 22.9,and 25.0±0.2 degrees 2 theta as measured by x-ray powder diffractionusing an x-ray wavelength of 1.54 Å.

Provided herein as Embodiment 9 is the compound of any one ofEmbodiments 1-3, wherein the compound is characterized by the powderX-ray diffraction pattern substantially as shown in FIG. 5 as measuredby x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

Provided herein as Embodiment 10 is the compound of any one ofEmbodiments 1-9, wherein the compound is characterized by a differentialscanning calorimetry thermogram comprising an endotherm with an onset ofabout 293° C.

Provided herein as Embodiment 11 is the compound of any one ofEmbodiments 1-10, wherein the compound is characterized by athermogravimetric analysis thermogram comprising a weight loss of about0.2% when heated from about 25° C. to about 275° C.

Provided herein as Embodiment 12 is the compound of any one ofEmbodiments 1-11, wherein the compound is characterized by ¹³C solidstate NMR comprising at least three peaks selected from peaks atapproximately 12, 13, 16, 21, 23, 31, 33, 38, 42, 44, 47, 50, 54, 107,110, 111, 123, 124, 127, 128, 132, 145, 146, 150, 154, 156, 158, 160,162, 166, 167, and 168 ppm.

Provided herein as Embodiment 13 is the compound of any one ofEmbodiments 1-11, wherein the compound is characterized by ¹³C solidstate NMR comprising at least five peaks selected from peaks atapproximately 12, 13, 16, 21, 23, 31, 33, 38, 42, 44, 47, 50, 54, 107,110, 111, 123, 124, 127, 128, 132, 145, 146, 150, 154, 156, 158, 160,162, 166, 167, and 168 ppm.

Provided herein as Embodiment 14 is the compound of any one ofEmbodiments 1-11, wherein the compound is characterized by ¹³C solidstate NMR comprising at least seven peaks selected from peaks atapproximately 12, 13, 16, 21, 23, 31, 33, 38, 42, 44, 47, 50, 54, 107,110, 111, 123, 124, 127, 128, 132, 145, 146, 150, 154, 156, 158, 160,162, 166, 167, and 168 ppm.

Provided herein as Embodiment 15 is the compound of any one ofEmbodiments 1-11, wherein the compound is characterized by ¹³C solidstate NMR comprising peaks at approximately 12, 13, 16, 21, 23, 31, 33,38, 42, 44, 47, 50, 54, 107, 110, 111, 123, 124, 127, 128, 132, 145,146, 150, 154, 156, 158, 160, 162, 166, 167, and 168 ppm.

Provided herein as Embodiment 16 is the compound of any one ofEmbodiments 1-11, wherein the compound is characterized by ¹³C solidstate NMR substantially as depicted in FIG. 8.

Provided herein as Embodiment 17 is the compound of any one ofEmbodiments 1-16, wherein the compound is characterized by ¹⁹F solidstate NMR comprising peaks at approximately −49, −60, −79, −90, −109,−120, −138, −150, −168, and −179 ppm.

Provided herein as Embodiment 18 is the compound of any one ofEmbodiments 1-16, wherein the compound is characterized by ¹⁹F solidstate NMR substantially as depicted in FIG. 9.

Provided herein as Embodiment 19 is the compound of any one ofEmbodiments 1-18, wherein the compound is substantially pure.

Provided herein as Embodiment 20 is a pharmaceutical compositioncomprising the compound of any one of Embodiments 1-19 and apharmaceutically acceptable excipient.

Provided herein as Embodiment 21 is the pharmaceutical composition ofEmbodiment 20, wherein the pharmaceutical composition is a dosage formfor oral administration.

Provided herein as Embodiment 22 is the pharmaceutical composition ofEmbodiment 20 or 21, wherein the dosage form is a solid dosage form.

Provided herein as Embodiment 23 is the pharmaceutical composition ofEmbodiment 22, wherein the solid dosage form is a tablet.

Provided herein as Embodiment 24 is the pharmaceutical composition ofany one of Embodiments 20-23, wherein the pharmaceutical compositioncomprises 120 mg of the compound.

Provided herein as Embodiment 25 is a compound of any one of Embodiments1-19 or the pharmaceutical composition of any one of Embodiments 20-24for use as a medicament.

Provided herein as Embodiment 26 is a compound of any one of Embodiments1-19 or the pharmaceutical composition of any one of Embodiments 20-24for use in treating cancer having a KRAS G12C mutation.

Provided herein as Embodiment 27 is the compound or the pharmaceuticalcomposition for use of Embodiment 26, wherein the cancer having a KRASG12C mutation is lung cancer, pancreatic cancer, or colorectal cancer.

Provided herein as Embodiment 28 is the compound or the pharmaceuticalcomposition for use of Embodiment 26, wherein the cancer having a KRASG12C mutation is non-small cell lung cancer.

Provided herein as Embodiment 29 is the compound or the pharmaceuticalcomposition for use of Embodiment 26, wherein the cancer having a KRASG12C mutation is pancreatic cancer.

Provided herein as Embodiment 30 is the compound or the pharmaceuticalcomposition for use of Embodiment 26, wherein the cancer having a KRASG12C mutation is colorectal cancer.

Provided herein as Embodiment 31 is a use of the compound of any one ofEmbodiments 1-19 or the pharmaceutical composition of any one ofEmbodiments 20-24 in the preparation of a medicament for treating cancerhaving a KRAS G12C mutation.

Provided herein as Embodiment 32 is the use of Embodiment 31, whereinthe cancer having a KRAS G12C mutation is lung cancer, pancreaticcancer, or colorectal cancer.

Provided herein as Embodiment 33 is the use of Embodiment 31, whereinthe cancer having a KRAS G12C mutation is non-small cell lung cancer.

Provided herein as Embodiment 34 is the use of Embodiment 31, whereinthe cancer having a KRAS G12C mutation is pancreatic cancer.

Provided herein as Embodiment 35 is the use of Embodiment 31, whereinthe cancer having a KRAS G12C mutation is colorectal cancer.

Provided herein as Embodiment 36 is a method of treating a cancer havinga KRAS G12C mutation in a patient in need thereof, the method comprisingadministering to the patient a therapeutically effective amount of thecompound of any one of Embodiments 1-19.

Provided herein as Embodiment 37 is the method of Embodiment 36, whereinthe cancer having a KRAS G12C mutation is lung cancer, pancreaticcancer, or colorectal cancer.

Provided herein as Embodiment 38 is the method of Embodiment 36, whereinthe cancer having a KRAS G12C mutation is small cell lung cancer.

Provided herein as Embodiment 39 is the method of Embodiment 36, whereinthe cancer having a KRAS G12C mutation is pancreatic cancer.

Provided herein as Embodiment 40 is the method of Embodiment 36, whereinthe cancer having a KRAS G12C mutation is colorectal cancer.

Provided herein as Embodiment 41 is the compound, use, or method of anyone of Embodiments 25-40, wherein the compound is administered at atotal daily dose of 960 mg.

Provided herein as Embodiment 42 is the compound, use, or method of anyone of Embodiments 25-41, wherein the compound is administered to anadult.

Provided herein as Embodiment 43 is the compound of any one ofEmbodiments 1-3, wherein the compound is characterized by a powder X-raydiffraction pattern comprising peaks at 7.3, 9.8, 10.1, 11.3, 13.3, and17.2±0.2 degrees 2 theta as measured by x-ray powder diffraction usingan x-ray wavelength of 1.54 Å.

Provided herein as Embodiment 44 is the compound of any one ofEmbodiments 1-3, wherein the compound is characterized by a powder X-raydiffraction pattern comprising at least three peaks selected from 7.3,9.8, 10.1, 10.4, 11.3, 11.5, 11.9, 13.3, 14.3, 14.7, 17.2, and 18.4±0.2degrees 2 theta as measured by x-ray powder diffraction using an x-raywavelength of 1.54 Å.

Provided herein as Embodiment 45 is the compound of any one ofEmbodiments 1-3, wherein the compound is characterized by a powder X-raydiffraction pattern comprising at least five peaks selected from 7.3,9.8, 10.1, 10.4, 11.3, 11.5, 11.9, 13.3, 14.3, 14.7, 17.2, and 18.4±0.2degrees 2 theta as measured by x-ray powder diffraction using an x-raywavelength of 1.54 Å.

Provided herein as Embodiment 46 is the compound of any one ofEmbodiments 1-3, wherein the compound is characterized by a powder X-raydiffraction pattern comprising at least seven peaks selected from 7.3,9.8, 10.1, 10.4, 11.3, 11.5, 11.9, 13.3, 14.3, 14.7, 17.2, and 18.4±0.2degrees 2 theta as measured by x-ray powder diffraction using an x-raywavelength of 1.54 Å.

Provided herein as Embodiment 47 is the compound of any one ofEmbodiments 1-3, wherein the compound is characterized by a powder X-raydiffraction pattern comprising peaks at 7.3, 9.8, 10.1, 10.4, 11.3,11.5, 11.9, 13.3, 14.3, 14.7, 17.2, and 18.4±0.2 degrees 2 theta asmeasured by x-ray powder diffraction using an x-ray wavelength of 1.54Å.

Provided herein as Embodiment 48 is the compound of any one ofEmbodiments 1-3, wherein the compound is characterized by the powderX-ray diffraction pattern substantially as shown in FIG. 10 as measuredby x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

Provided herein as Embodiment 49 is the compound of any one ofEmbodiments 1-3 and 43-48, wherein the compound is characterized by adifferential scanning calorimetry thermogram comprising an endothermwith an onset of about 193° C.

Provided herein as Embodiment 50 is the compound of any one ofEmbodiments 1-3 and 43-49, wherein the compound is characterized byhaving a thermogravimetric analysis thermogram comprising a weight lossof about 1% to about 1.8% when heated from about 25° C. to about 250° C.

Provided herein as Embodiment 51 is the compound of any one ofEmbodiments 1-3 and 43-50, wherein the compound is characterized by ¹³Csolid state NMR comprising peaks at approximately 16, 18, 19, 20, 23,25, 31, 32, 38, 40, 43, 46, 51, 57, 105, 107, 110, 117, 120, 123, 124,125, 128, 132, 149, 152, 155, 158, 159, 163, and 166 ppm.

Provided herein as Embodiment 52 is the compound of any one ofEmbodiments 1-3 and 43-50, wherein the compound is characterized by ¹³Csolid state NMR substantially as depicted in FIG. 13.

Provided herein as Embodiment 53 is the compound of any one ofEmbodiments 1-3 and 43-52, wherein the compound is characterized by ¹⁹Fsolid state NMR, comprising peaks at approximately −59, −62, −89, −92,−119, −122, −148, −151, −179 and −181 ppm.

Provided herein as Embodiment 54 is the compound of any one ofEmbodiments 1-3 and 43-52, wherein the compound is characterized by ¹⁹Fsolid state NMR substantially as depicted in FIG. 14.

Provided herein as Embodiment 55 is the compound of any one ofEmbodiments 43-54, wherein the compound is substantially pure.

Provided herein as Embodiment 56 is a pharmaceutical compositioncomprising the compound of any one of Embodiments 43-55 and apharmaceutically acceptable excipient.

Provided herein as Embodiment 57 is the compound of any one ofEmbodiments 1-3, wherein the compound is characterized by a powder X-raydiffraction pattern comprising peaks at 6.3, 8.4, 9.5, and 16.0±0.2degrees 2 theta as measured by x-ray powder diffraction using an x-raywavelength of 1.54 Å.

Provided herein as Embodiment 58 is the compound of any one ofEmbodiments 1-3, wherein the compound is characterized by a powder X-raydiffraction pattern comprising at least three peaks selected from 6.3,8.4, 9.5, 10.4, 14.9, 15.4, 15.5, 16.0, and 17.6±0.2 degrees 2 theta asmeasured by x-ray powder diffraction using an x-ray wavelength of 1.54Å.

Provided herein as Embodiment 59 is the compound of any one ofEmbodiments 1-3, wherein the compound is characterized by a powder X-raydiffraction pattern comprising at least five peaks selected from 6.3,8.4, 9.5, 10.4, 14.9, 15.4, 15.5, 16.0, and 17.6±0.2 degrees 2 theta asmeasured by x-ray powder diffraction using an x-ray wavelength of 1.54Å.

Provided herein as Embodiment 60 is the compound of any one ofEmbodiments 1-3, wherein the compound is characterized by a powder X-raydiffraction pattern comprising at least seven peaks selected from 6.3,8.4, 9.5, 10.4, 14.9, 15.4, 15.5, 16.0, and 17.6±0.2 degrees 2 theta asmeasured by x-ray powder diffraction using an x-ray wavelength of 1.54Å.

Provided herein as Embodiment 61 is the compound of any one ofEmbodiments 1-3, wherein the compound is characterized by a powder X-raydiffraction pattern comprising peaks at 6.3, 8.4, 9.5, 10.4, 14.9, 15.4,15.5, 16.0, and 17.6±0.2 degrees 2 theta as measured by x-ray powderdiffraction using an x-ray wavelength of 1.54 Å.

Provided herein as Embodiment 62 is the compound of any one ofEmbodiments 1-3, wherein the compound is characterized by the powderX-ray diffraction pattern substantially as shown in FIG. 15 as measuredby x-ray powder diffraction using an x-ray wavelength of 1.54 Å.

Provided herein as Embodiment 63 is the compound of any one ofEmbodiments 1-3 and 57-62, wherein the compound is characterized by adifferential scanning calorimetry thermogram comprising an endothermwith an onset of about 194° C.

Provided herein as Embodiment 64 is the compound of any one ofEmbodiments 1-3 and 57-63, wherein the compound is characterized byhaving an approximate negligible weight loss when heated from about 25°C. to about 250° C.

Provided herein as Embodiment 65 is the compound of any one ofEmbodiments 57-64, wherein the compound is substantially pure.

Provided herein as Embodiment 66 is a pharmaceutical compositioncomprising the compound of any one of Embodiments 57-65 and apharmaceutically acceptable excipient.

Provided herein as Embodiment 67 is the compound of Embodiment 1 or 2,wherein the compound is a crystalline hydrate form of Compound 1.

Provided herein as Embodiment 68 is the compound of any one ofEmbodiments 1, 2, and 67, wherein the compound is characterized by apowder X-ray diffraction pattern comprising peaks at 6.9, 8.0, 9.6,12.4, and 13.1±0.2 degrees 2 theta as measured by x-ray powderdiffraction using an x-ray wavelength of 1.54 Å.

Provided herein as Embodiment 69 is the compound of any one ofEmbodiments 1, 2, and 67, wherein the compound is characterized by apowder X-ray diffraction pattern comprising at least three peaksselected from 4.0, 4.4, 4.8, 6.9, 8.0, 8.8, 9.6, 11.3, 12.4, 13.0, 13.1,14.6, 14.9, 15.2, 16.6, 17.3, 17.4, 17.9, and 19.5±0.2 degrees 2 thetaas measured by x-ray powder diffraction using an x-ray wavelength of1.54 Å.

Provided herein as Embodiment 70 is the compound of any one ofEmbodiments 1, 2, and 67, wherein the compound is characterized by apowder X-ray diffraction pattern comprising at least five peaks selectedfrom 4.0, 4.4, 4.8, 6.9, 8.0, 8.8, 9.6, 11.3, 12.4, 13.0, 13.1, 14.6,14.9, 15.2, 16.6, 17.3, 17.4, 17.9, and 19.5±0.2 degrees 2 theta asmeasured by x-ray powder diffraction using an x-ray wavelength of 1.54Å.

Provided herein as Embodiment 71 is the compound of any one ofEmbodiments 1, 2, and 67, wherein the compound is characterized by apowder X-ray diffraction pattern comprising at least seven peaksselected from 4.0, 4.4, 4.8, 6.9, 8.0, 8.8, 9.6, 11.3, 12.4, 13.0, 13.1,14.6, 14.9, 15.2, 16.6, 17.3, 17.4, 17.9, and 19.5±0.2 degrees 2 thetaas measured by x-ray powder diffraction using an x-ray wavelength of1.54 Å.

Provided herein as Embodiment 72 is the compound of any one ofEmbodiments 1, 2, and 67, wherein the compound is characterized by apowder X-ray diffraction pattern comprising peaks at 4.0, 4.4, 4.8, 6.9,8.0, 8.8, 9.6, 11.3, 12.4, 13.0, 13.1, 14.6, 14.9, 15.2, 16.2, 16.4,16.6, 17.3, 17.4, 17.9, and 19.5±0.2 degrees 2 theta as measured byx-ray powder diffraction using an x-ray wavelength of 1.54 Å.

Provided herein as Embodiment 73 is the compound of any one ofEmbodiments 1, 2, and 67, wherein the compound is characterized by thepowder X-ray diffraction pattern substantially as shown in FIG. 18 asmeasured by x-ray powder diffraction using an x-ray wavelength of 1.54Å.

Provided herein as Embodiment 74 is the compound of any one ofEmbodiments 1, 2, and 67-73, wherein the compound is characterized by adifferential scanning calorimetry thermogram comprising an endothermwith an onset of about 91° C.

Provided herein as Embodiment 75 is the compound of any one ofEmbodiments 1, 2, and 67-74, wherein the compound is characterized byhaving a thermogravimetric analysis thermogram comprising an approximate11% weight loss when heated from about 39° C. to about 160° C.

Provided herein as Embodiment 76 is the compound of any one ofEmbodiments 67-75, wherein the compound is substantially pure.

Provided herein as Embodiment 77 is a pharmaceutical compositioncomprising the compound of any one of Embodiments 67-76 and apharmaceutically acceptable excipient.

Provided herein as Embodiment 78 is the compound of Embodiment 1 or 2,wherein the compound is a crystalline solvate form of Compound 1.

Provided herein as Embodiment 79 is the compound of Embodiment 78,wherein the compound is a solvate with tetrahydrofuran, acetonitrile,methyl ethylketone, ethyl acetate, dichloromethane, acetone, p-dioxane,methanol, isopropyl alcohol, or ethanol.

Provided herein as Embodiment 80 is a compound, wherein the compound isan amorphous form of6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one(Compound 1) or an atropisomer thereof.

Provided herein as Embodiment 81 is the compound of Embodiment 80,wherein the compound is the M atropisomer of Compound 1.

Provided herein as Embodiment 82 is the compound of Embodiments 80 or81, wherein the compound is characterized by the powder X-raydiffraction pattern substantially as shown in FIG. 5 as measured byx-ray powder diffraction using an x-ray wavelength of 1.54 Å.

Provided herein as Embodiment 83 is the compound of any one ofEmbodiments 80-82, wherein the compound is characterized by adifferential scanning calorimetry thermogram comprising an endothermwith an onset of about 144° C.

Provided herein as Embodiment 84 is the compound of any one ofEmbodiments 80-83, wherein the compound is characterized by athermogravimetric analysis thermogram comprising a weight loss of about1.5% when heated from about 25° C. to about 275° C.

Provided herein as Embodiment 85 is the compound of any one ofEmbodiments 80-84, wherein the compound is characterized by ¹⁹F solidstate NMR comprising peaks at approximately −86, −96, −116, −127, −146,and −156 ppm.

Provided herein as Embodiment 86 is the compound of any one ofEmbodiments 80-85, wherein the compound is characterized by ¹⁹F solidstate NMR substantially as depicted in FIG. 4.

Provided herein as Embodiment 87 is the compound of any one ofEmbodiments 80-86, wherein the compound is substantially pure.

Provided herein as Embodiment 88 is a pharmaceutical compositioncomprising the compound of any one of Embodiments 80-87 and apharmaceutically acceptable excipient.

Provided herein as Embodiment 89 is a pharmaceutical compositioncomprising (1) the compound of any one of Embodiments 4-18, (2) thecompound of any one of Embodiments 43-54, (3) the compound of any one ofEmbodiments 57-64, (4) the compound of any one of Embodiments 67-75, or(5) the compound of any one of Embodiments 80-86, or any mixturesthereof, and a pharmaceutically acceptable excipient.

Crystallization Techniques Anti-Solvent Precipitation

Solutions of the compounds of the disclosure were prepared in varioussolvents and an anti-solvent was then added. The solids that formed wereisolated and analyzed.

Alternatively, solutions of the compounds of the disclosure wereprepared in various solvents, an anti-solvent was then added and thesamples were allowed to evaporate. The solids that formed were isolatedand analyzed.

Alternatively, solutions of the compounds of the disclosure wereprepared in various solvents, an anti-solvent was then added and thesamples were cooled to 2° C. to 8° C. The solids that formed wereisolated and analyzed.

Sonication

Solutions or suspensions of the compounds of the disclosure wereprepared in various solvents and sonicated in an ice bath for 90-180minutes. The solids were isolated and analyzed.

Slow Cool

Saturated solutions of the compounds of the disclosure were prepared invarious solvents at either ambient or elevated temperature. Samplesprepared at elevated temperature were allowed to cool to ambient or 2-8°C. The solids that formed were isolated and analyzed.

Evaporation

Solutions of the compounds of the disclosure were prepared in varioussolvents. Once complete dissolution was observed, the solvent wasevaporated by vacuum at ambient or heated temperatures. The solids thatformed were isolated and analyzed.

Slow Evaporation

Solutions of the compounds of the disclosure were prepared in varioussolvents. Once complete dissolution was observed, the solution wasallowed to evaporate at ambient in a partially covered vial, with orwithout a blanket of nitrogen gas. The solids that formed were isolatedand analyzed.

Alternatively, solutions of the compounds of the disclosure wereprepared followed by sonication for about 90 minutes. Followingsonication the samples were allowed to evaporate. Experiments thatyielded glasses, were reworked by slurrying the materials with a 15 foldaddition of anti-solvent (hexane at 50° C. or water at roomtemperature). Any resulting solids were isolated and analyzed.

Stress Experiments

Solutions or suspensions of the compounds of the disclosure wereprepared in various solvents followed by sonication for 60 minutes.Samples were then stirred to 30° C. for 24-72 hours, followed bystirring at 50° C. for 24 hours. Samples were analyzed by XRPD at eachstage before final isolation and analysis.

Slurry Experiments

Solutions of the compounds of the disclosure were prepared by addingenough solids to a given solvent so that excess solids were present. Allforms described below can be obtained from various solvents, including,but not limited, to the specific solvents described in the Examples. Themixture was then agitated in a sealed vial at either ambient or elevatedtemperature. After a given amount of time, the solids were isolated byvacuum or centrifuge filtration and analyzed.

Analytical Techniques X-Ray Powder Diffraction (XRPD

X-ray powder diffraction data was obtained using the Phillips X-rayautomated powder diffractometer (X'Pert) that was equipped with a fixedslit and a real time multi strip (RTMS) detector. The radiation was CuKα(1.54 Å) and the voltage and current were 45 kV and 40 mA, respectively.Data were collected at room temperature from 3.0 to 40.0 degree 2-theta;step size was 0.0167 degrees; counting time was 15.240 seconds. Thestage was rotated at a revolution time of 1.0 second.

Alternatively, X-ray powder diffraction data was obtained using thePANalytical Empyrean automated powder diffractometer that was equippedwith a soller slit, beam stop, short antiscatter extension, antiscatterknife edge and a scanning position-sensitive detector (X'Celerator). Theradiation was CuKα (1.54 Å). A specimen of the sample was sandwichedbetween 3 um thick films and analyzed in transmission geometry.

Alternatively, X-ray powder diffraction data was obtained using thePANalytical X'Pert PRO X-ray diffraction system that was equipped with aprogrammable divergence slit and a real time multi strip (RTMS)detector. The radiation was CuKα (1.54 Å) and the voltage and currentwere 45 kV and 40 mA, respectively. Data were collected at roomtemperature from 3.0 to 30.0 or 5 to 45 degrees 2-theta; step size was0.0334 degrees. The stage was rotated at a revolution time of 2.0seconds.

It is noted that peak shift of about +/−0.2 degrees can occur in XRPDpatterns and could be caused by factors such as sample preparation andinstrument alignment.

Thermogravimetric Analysis (TGA)

Thermogravimetric analysis was performed on a TGA Discovery Series, TAInstruments. Samples were analyzed under nitrogen at heating rates of10° C./min over a temperature range from 25° C. to 325° C.

Differential Scanning Calorimetry (DSC)

Differential scanning calorimetry data was collected using standard DSCmode (Discovery Series, TA Instruments). A heating rate of 10° C./minwas employed over a temperature range from 25° C. to 350° C. Analysiswas run under nitrogen and samples were loaded in aluminum pans. Indiumwas used as a calibration standard.

Solid State NMR

Approximately 100 mg of sample was packed into a 4 mm ceramic rotorusing the SSNMR packing tool. SSNMR spectra were acquired on a BrukerAvance III 500 MHz WB spectrometer. ¹⁹F spectra were collected using aBruker double resonance MAS probe operating at a ¹H resonance frequencyof 500 MHz. A 4-mm H/F/X spinning probe operating at a spinningfrequency of 14 kHz was used for all experiments. For ¹⁹F measurement, a4 us pi/2 pulse was used and ¹H decoupling was carried out using aspinal 64 sequence. A recycle delay of 1.26*T1 was used for optimalS/N/time.

EXAMPLES Example 1: Identification of Solid State Forms of Compound 1

Within the pharmaceutical research and development field, theinvestigation of a suitable solid-state form represents a crucial step.Investigating a solid-state form comprises several decisions, mainly theinvestigation of an anhydrous, salt or co-crystal form and theinvestigation of a polymorph of the respective anhydrous, salt orco-crystal. During a lead optimization program, several properties ofresearch compounds are optimized, typically leading to one or a fewcandidates that continue into exploratory development programs.Typically, in the assessment and optimization of physical chemicalparameters during lead optimization, the main focus is on solubility. Inthe present case, Compound 1 has good solubility features. Beyond theoptimization of solubility, further physical chemical parameters, suchas (1) melting point, (2) thermal behavior, (3) hygroscopicity, (4)crystal habit, (5) polymorphic behavior or physical stability, (6)impurity profile, and (7) chemical stability of the anhydrous or saltform, must be borne in mind when investigating the salt. The meltingpoint of a drug, either as a free base, acid or salt form, should behigher than a certain threshold to allow processing steps such as dryingor tabletting. The assessment of thermal behavior, which is typicallydone by thermogravimetry (TGA) and differential scanning calorimetry(DSC), also includes solid-solid phase transitions. These may be eitherenantiotropic or monotropic and can be related to the conversion of onepolymorph to another or one pseudo-polymorph to anotherpseudo-polymorph—e.g. a lower solvate or hydrate—or a true polymorph.Hygroscopicity plays a key role in the evaluation of solid-state forms,as this property is highly relevant for many process steps such asdrying, storage, blending, granulation, to name but a few.Hygroscopicity can be investigated by dynamic vapor sorption (DVS).Basically, this technique yields information on the amount of moisturethat is taken up by the compound at a certain relative humidity level.Discussing thermal behavior and hygroscopicity represents the link toanother parameter that has to be considered in anhydrous or saltinvestigation: a manageable polymorphic behavior is required for ananhydrous or salt form to continue in pharmaceutical development.Therefore, at least a brief assessment of polymorphism is typicallycarried out in an anhydrous or salt-investigation procedure. In thissense, a manageable polymorphic behavior is not equivalent to theexistence of only one or two polymorphic forms, but rather to render asituation where the conversion of polymorphic forms that are notequivalent. Crystal habits can influence anhydrous or saltinvestigations, and optimization in many cases means moving away a drugin the form of needle-shaped crystals towards e.g. platelets or evencubic crystals exhibiting better flowability. Salt investigation can bea tool to improve impurity profiles of drugs since pharmaceutical saltsoften exhibit crystal structures that are quite different from thestructure of the corresponding free base or acid.

Polymorph and Salt Screen

Accordingly, a polymorph and salt screen of Compound 1 was conducted.Crystalline chloride, phosphate, and mesylate salts as well ascrystalline anhydrate, hydrate and solvate forms were identified. Noneof the identified salts displayed particularly advantageous thermalproperties based on DSC data or appeared of lower crystallinity. Of theseveral remaining free base polymorphs, including the hydrate andsolvates, the crystalline anhydrous Form I showed surprising andunexpected advantages.

First, the crystalline anhydrous Form I of Compound 1 is the mostthermodynamically stable polymorph identified in the screening process.The crystalline anhydrous Form II and III described herein below convertto crystalline anhydrous Form I upon heating or slurrying.

Specifically, crystalline anhydrous Form II converts to crystallineanhydrous Form I upon heating and recrystallization at 193° C.Crystalline anhydrous Form II converts to crystalline anhydrous Form Iupon slurrying in water at 90° C. for 1 hour. A mixture of crystallineanhydrous Form I and crystalline anhydrous Form II converts tocrystalline anhydrous Form I upon slurrying in 90/10 v/vwater/acetonitrile at RT for 7 days. A mixture of crystalline anhydrousForm I and crystalline anhydrous Form II converts to crystallineanhydrous Form I upon slurrying in heptane at 80° C. for 1 day.

Crystalline anhydrous Form III melts at 180° C. Crystalline anhydrousForm III converts to crystalline anhydrous Form I upon melting andrecrystallization at 220° C. A mixture of crystalline anhydrous Form Iand crystalline anhydrous Form III converts to crystalline anhydrousForm I upon slurrying in ethanol at RT for 10 days. A mixture ofcrystalline anhydrous Form I and crystalline anhydrous Form III convertsto crystalline anhydrous Form I upon slurrying in methanol at RT for 10days.

The high melting point of crystalline anhydrous Form I is a furtherindicator of its thermodynamic stability (DSC endotherm onset of about293° C.).

Second, crystalline anhydrous Form I is less hygroscopic compared tocrystalline anhydrous Forms II and III (Form I absorbed 0.5-1.0% wtmoisture between 0 and 90% RH at 25° C.; Form II absorbed 2-2.5% wtmoisture between 0 and 90% RH at 25° C.; Form III absorbed 7.0% wtmoisture between 0-95% RH at 25° C.).

Moreover, crystalline anhydrous Form I was physically and chemicallystable in the solid state, showing no degradation peaks by HPLC or anychanges in the investigated solid state properties, including XRPD,melting point onset and heat of fusion by DSC, and volatiles content byTGA, for 14 weeks at 25° C./60% RH, 40° C./75% RH, 40° C./ambient RH,and 60° C./ambient RH. Furthermore, crystalline anhydrous Form I wasstable in an excipient compatibility study in 3 prototype blends thatwere stored for 4 weeks at 40° C./75% RH. Crystalline anhydrous Form Iwas also stable to ultraviolet and visible light in the solid state.

Accordingly, crystalline anhydrous Form I shows advantageous andunexpected overall properties, in particular when compared with otherforms and salts identified.

Polymorph Screen

A polymorph screen to generate the different solid forms of the Matropisomer of6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one(Compound 1) was carried out as described below. As a matter ofconvenience, “Compound 1” as referred to in the Examples that follow isto be understood to be the M atropisomer of Compound 1.

Example 1

Compound 1 can be made according to the procedure disclosed in USPublication 2018/0334454 published on Nov. 22, 2018, which is hereinincorporated by reference in its entirety.

Amorphous Form I of Compound 1 was prepared by rotary evaporation fromMeOH with secondary drying under vacuum at RT.

The relative peak areas of the amorphous form of the XRPD, TGA, DSC and¹⁹F SSNMR are represented in FIGS. 1, 2, 3 and 4.

Differential scanning calorimetry (DSC) thermogram comprising anendotherm with an onset of about 144° C.

Thermogravimetric analysis (TGA) thermogram comprising a weight loss ofabout 1.5% when heated from about 25° C. to about 275° C.

¹⁹F SSNMR: −86, −96, −116, −127, −146 and −156 ppm.

A number of anhydrous and hydrate forms of Compound 1 were investigated(see Table 1 below). Further characterization of these crystallineforms, such as melting point, thermal behavior, hygroscopicity, crystalhabit, particle size, polymorphic behavior, stability, and purity, wereinvestigated. These forms were characterized by methods including XRPD,TGA, and DSC analysis. Rel. Int % is the percent relative intensitybased on the largest peak.

FIG. 21 illustrates the overlay of crystalline anhydrous Forms I, II,III and the variable hydrate Form I of Compound 1 (Forms I-III andvariable hydrate Form I are in order from top to bottom).

TABLE 1 XRPD Differentiating Peaks Free Base Form Peaks Unique to EachForm (KA1°) Form I 9.0 12.0 12.6 19.0 — — Form II 7.3 9.8 10.1 11.3 13.317.2 Form III 6.3 8.4 9.5 16.0 — — Hydrate Form I 6.9 8.0 9.6 12.4 13.1—

Example 2: Preparation of Crystalline Anhydrous Form I of Compound 1

Crystalline anhydrous Form I was prepared by charging 1.5 g ofcrystalline anhydrous Form II of Compound 1 with 10 mL of water to forma slurry. The slurry was heated to 90° C. for 2 h, then stirredovernight at RT. The solids were filtered, dried under vacuum andidentified as crystalline anhydrous Form I by XRPD. DSC endotherm onsetof about 292.6° C., TGA comprising a weight loss of about 0.2% whenheated from about 25° C. to about 275° C.

The crystalline anhydrous Form I prepared above was characterized byproton NMR, X-ray powder diffraction (XRPD) data (FIG. 5), DSC (FIG. 6),TGA (FIG. 7), carbon 13 SSNMR (FIG. 8), and ¹⁹F SSNMR (FIG. 9).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.93 (d, J=6.84 Hz, 3H) 1.07 (d, J=6.63Hz, 3H) 1.35 (d, J=6.84 Hz, 3H) 1.90 (s, 3H) 2.66-2.75 (m, 1H) 3.14 (brt, J=11.20 Hz, 1H) 3.59-3.75 (m, 2H) 3.97-4.08 (m, 1H) 4.08-4.22 (m, 1H)4.22-4.43 (m, 2H) 4.90 (br s, 1H) 5.74-5.79 (m, 1H) 6.21 (br d, J=17.00Hz, 1H) 6.65-6.75 (m, 2H) 6.79-6.92 (m, 1H) 7.18 (d, J=4.98 Hz, 1H)7.23-7.31 (m, 1H) 8.22-8.33 (m, 1H) 8.38 (d, J=4.77 Hz, 1H) 10.19 (s,1H)

¹³C SSNMR: 12, 13, 16, 21, 23, 31, 33, 38, 42, 44, 47, 50, 54, 107, 110,111, 123, 124, 127, 128, 132, 145, 146, 150, 154, 156, 158, 160, 162,166, 167.7 and 168 ppm.

¹⁹F SSNMR: −49, −60, −79, −90, −109, −120, −138, −150, −168 and −179ppm.

TABLE 2 XRPD data of the crystalline anhydrous Form I of Compound 1 XRPDPeak Table: Pos. Rel. Int. [°2 Th.] [%] 8.8 72.02 9.0 32.38 10.8 89.4812.0 17.57 12.6 5.21 12.8 7.83 13.6 70.38 13.9 8.16 14.2 64.52 14.315.98 15.0 54.34 15.4 34.78 15.5 11.84 17.4 10.60 17.6 11.10 18.0 22.2818.6 20.76 18.7 41.59 19.0 100.00 19.2 13.83 19.9 34.21 20.0 20.81 20.22.92 20.9 8.05 21.2 2.59 21.7 14.40 22.0 9.77 22.2 16.27 22.5 18.45 22.921.27 23.1 14.15 23.7 15.87 23.9 10.39 25.0 19.32 25.3 4.26 25.6 1.9025.8 6.05 26.1 7.93 26.3 4.28 26.6 12.27 26.8 8.19 27.3 7.42 27.8 3.3128.0 11.20 28.5 3.83 28.8 8.53 29.1 2.01 29.4 13.68 29.7 9.66 30.2 13.6030.9 1.84 31.3 1.53 31.5 5.71 31.7 3.54 31.9 1.13 32.3 1.55 32.6 1.6932.8 2.47 33.0 2.11 33.6 3.23 33.9 5.14 34.2 3.90 34.7 0.67 34.9 1.7635.0 1.62 35.4 1.10 35.8 2.43 36.5 0.59 37.0 4.04 37.0 2.30 37.3 0.8037.7 0.66 38.0 1.27 38.3 2.60 38.4 4.02 39.1 0.51 39.4 1.88 39.8 0.90

Example 3: Preparation of the Anhydrous Form II of the Compound 1

The crystalline anhydrous Form II of Compound 1 was prepared by charging0.987 g of amorphous Compound 1 with 15 mL MeOH to produce a slurry. Theisolated solids were identified as crystalline anhydrous Form II byXRPD.

DSC onset of about 192.5° C., TGA comprising a weight loss of about 1%to about 1.8% when heated from about 25° C. to about 250° C.

The crystalline anhydrous Form II of Compound 1 prepared above wascharacterized by proton NMR, X-ray powder diffraction (XRPD) data (FIG.10), DSC (FIG. 11), TGA (FIG. 12), carbon 13 SSNMR (FIG. 13), and ¹⁹FSSNMR (FIG. 14).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.93 (d, J=6.63 Hz, 4H) 1.07 (d, J=6.84Hz, 4H) 1.35 (d, J=6.63 Hz, 4H) 1.90 (s, 3H) 2.60-2.76 (m, 1H) 3.11-3.28(m, 2H) 3.68 (br d, J=13.89 Hz, 2H) 4.08 (d, J=5.18 Hz, 2H) 4.32 (br d,J=13.68 Hz, 2H) 4.90 (br s, 1H) 5.74-5.79 (m, 1H) 6.21 (br d, J=16.17Hz, 1H) 6.65-6.76 (m, 2H) 6.80-6.92 (m, 1H) 7.18 (d, J=4.98 Hz, 1H)7.23-7.31 (m, 1H) 8.29 (br d, J=9.33 Hz, 1H) 8.38 (d, J=4.98 Hz, 1H)10.19 (s, 1H).

¹³C SSNMR: 16, 18, 19, 20, 23, 25, 31, 32, 38, 40, 43, 46, 51, 57, 105,107, 110, 117, 120, 123, 124, 125, 128, 132, 149, 152, 155, 158, 159,163 and 166 ppm.

¹⁹F SSNMR: −59, −62, −89, −92, −119, −122, −148, −151, −179 and −181ppm.

TABLE 3 XRPD data of the crystalline anhydrous Form II of Compound 1Pos. [°2Th.] Rel. Int. [%] Pos. [°2Th.] Rel. Int. [%] 7.3 55.69 27.19.80 9.8 22.74 27.3 12.94 10.1 13.34 27.9 2.58 10.4 26.87 28.3 6.04 11.3100.00 28.5 7.17 11.5 38.51 28.9 7.06 11.9 17.55 29.4 4.82 13.3 19.1929.6 6.76 14.3 37.78 30.7 4.35 14.7 63.63 31.2 4.41 14.9 20.80 31.5 1.7015.8 1.24 31.9 0.83 17.2 47.51 32.6 2.54 18.1 9.48 33.3 1.23 18.4 37.1734.0 0.53 18.6 6.86 34.6 1.58 19.2 31.06 35.0 1.66 19.8 5.10 35.4 2.3520.4 11.69 36.2 2.20 20.9 10.16 36.8 1.47 21.1 10.57 37.2 1.73 21.4 3.7838.0 2.55 21.7 3.26 38.4 4.75 22.1 18.04 38.8 2.68 22.4 12.23 22.6 4.7823.1 20.56 23.8 9.50 24.3 17.04 24.7 3.75 25.6 6.63 26.2 6.15

Example 4: Preparation of Crystalline Anhydrous Form III of Compound 1

The crystalline anhydrous Form III of Compound 1 was prepared by dryingthe acetone solvate Form I of Compound 1 by vacuum at ˜65-76° C. DSCendotherm onset of about 194° C., TGA comprising an approximatenegligible weight loss when heated from about 25° C. to about 250° C.

The crystalline anhydrous Form III of Compound 1 prepared above wascharacterized by proton NMR, X-ray powder diffraction (XRPD) data (FIG.15), DSC (FIG. 16), and TGA (FIG. 17).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.93 (d, J=6.82 Hz, 3H) 1.07 (d, J=6.61Hz, 3H) 1.35 (d, J=6.61 Hz, 2H) 1.90 (s, 2H) 2.64-2.80 (m, 1H) 3.14 (brt, J=10.66 Hz, 1H) 3.45-3.57 (m, 1H) 3.58-3.76 (m, 1H) 3.94-4.08 (m, 1H)4.14 (br d, J=13.00 Hz, 1H) 4.21-4.47 (m, 2H) 4.90 (br s, 1H) 5.76 (dd,J=10.44, 2.13 Hz, 1H) 6.21 (br d, J=16.84 Hz, 1H) 6.55-6.78 (m, 2H) 6.86(dt, J=16.20, 11.29 Hz, 1H) 7.13-7.21 (m, 1H) 7.21-7.33 (m, 1H)8.21-8.34 (m, 1H) 8.39 (d, J=4.90 Hz, 1H) 10.20 (br s, 1H).

TABLE 4 XRPD data of the Anhydrous Form III of Compound 1 Pos. [°2Th.]Rel. Int. [%] Pos. [°2Th.] Rel. Int. [%] 6.3 14.11 25.4 10.81 8.4 63.0625.9 5.35 9.5 84.68 26.7 17.58 10.4 12.93 26.8 5.18 12.8 6.80 27.2 10.3813.0 6.79 27.5 12.87 13.7 4.59 27.9 4.42 14.9 12.72 28.3 7.66 15.4 45.7328.6 15.70 15.5 69.05 29.3 3.10 16.0 79.08 29.7 1.70 16.6 8.35 30.2 1.0217.6 100.00 31.4 2.93 18.2 9.32 32.2 3.52 18.7 37.73 32.5 3.97 19.216.82 33.1 2.31 20.0 36.44 33.7 1.35 20.6 13.07 34.6 4.91 20.8 9.52 35.53.74 21.7 3.50 35.8 2.54 21.7 16.74 36.7 1.18 22.7 5.52 37.3 1.65 23.013.50 38.0 2.18 23.2 4.81 39.0 1.57 24.2 11.39 24.9 3.83

Example 5: Preparation of Variable Hydrate Form I of Compound 1

The variable hydrate Form I of Compound 1 was prepared by dissolvingCompound 1 in MeOH at RT, polish filtering then charging with aliquotsof water as an antisolvent until precipitation occurred. Solids wereisolated after stirring at RT for 13 days.

DSC first endotherm onset of about at 91° C., TGA comprising anapproximate 11% weight loss when heated from about 39° C. to about 160°C. (3.9 mol water).

Karl Fischer 10.63% (3.7 mol) water.

The crystalline variable hydrate Form I prepared above was characterizedby proton NMR, X-ray powder diffraction (XRPD) data (FIG. 18), DSC (FIG.19), and TGA (FIG. 20).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.94 (d, J=6.62 Hz, 3H) 1.08 (d, J=6.84Hz, 3H) 1.35 (d, J=6.63 Hz, 3H) 1.90 (s, 3H) 2.61-2.79 (m, 1H) 3.15 (brt, J=11.01 Hz, 1H) 3.40-3.58 (m, 2H) 3.59-3.84 (m, 3H) 3.86-4.09 (m, 1H)4.15 (br d, J=12.39 Hz, 1H) 4.21-4.47 (m, 3H) 4.90 (br s, 2H) 5.73-5.82(m, 1H) 6.15-6.21 (m, 1H) 6.23 (br d, J=4.92 Hz, 1H) 6.63-6.77 (m, 3H)6.78-7.03 (m, 2H) 7.14-7.31 (m, 3H) 8.14-8.35 (m, 1H) 8.39 (d, J=4.92Hz, 1H).

TABLE 5 XRPD data of the Crystalline Variable Hydrate Form I of Compound1 XRPD Peak Table: Pos. Rel. Int. Pos. Rel. Int. Pos. Rel. Int. [°2Th.][%] [°2Th.] [%] [°2Th.] [%] 4.0 10.00 16.6 29.36 25.3 31.05 4.4 12.0817.3 54.43 25.8 35.64 4.8 17.94 17.4 68.45 26.4 35.12 6.9 12.94 17.916.60 26.7 28.61 8.0 100.00 18.1 30.16 27.8 31.13 8.8 8.55 18.6 5.5128.7 25.99 9.6 26.66 19.3 27.13 29.2 25.20 10.8 10.41 19.5 35.91 30.614.61 11.3 13.06 19.8 13.20 31.5 19.08 12.4 36.89 20.4 8.31 32.2 8.8113.0 43.60 20.8 20.25 32.7 8.36 13.1 41.65 21.0 21.40 36.7 2.96 14.25.04 21.5 43.72 37.2 4.34 14.6 35.20 22.8 14.71 14.9 38.07 23.0 13.6115.2 40.25 23.6 14.15 15.7 7.44 24.1 28.65 16.2 40.04 24.6 20.05 16.417.22 25.1 28.24

Example 6: Preparation of Crystalline THF Solvate Form I of Compound 1

The crystalline THE solvate Form I of Compound 1 was prepared by placingamorphous Compound 1 in a small open vial then placing this vial insidea larger vial containing THE and capped to vapor stress the solids at RTfor 4 days.

DSC endotherm onset of about 165° C., TGA comprising an approximate13.4% weight loss when heated from about 130° C. to about 160° C. (1.2mol THF)

NMR 1.1 mol THE The crystalline THE solvate Form I prepared above wascharacterized by proton NMR, X-ray powder diffraction (XRPD) data (FIG.22), DSC (FIG. 23), and TGA (FIG. 24).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.94 (d, J=6.62 Hz, 3H) 1.08 (d, J=6.62Hz, 3H) 1.35 (d, J=6.62 Hz, 3H) 1.68-1.84 (m, 4H) 1.90 (s, 3H) 2.62-2.93(m, 1H) 3.15 (br t, J=11.33 Hz, 1H) 3.49-3.75 (m, 10H) 3.87-4.09 (m, 1H)4.09-4.21 (m, 1H) 4.22-4.47 (m, 4H) 4.91 (br s, 2H) 5.71-5.83 (m, 2H)6.21 (br dd, J=16.88, 4.70 Hz, 1H) 6.64-6.78 (m, 3H) 6.78-6.99 (m, 1H)7.14-7.22 (m, 1H) 7.28 (td, J=8.33, 7.05 Hz, 1H) 8.18-8.35 (m, 1H) 8.39(d, J=4.92 Hz, 1H) 10.21 (br s, 1H)

TABLE 6 XRPD data of the Crystalline THF solvate Form I of Compound 1XRPD Peak Table: Pos. [°2Th.] Rel. Int. [%] Pos. [°2Th.] Rel. Int. [%]7.0 54.90 26.9 1.62 9.0 100.00 27.3 2.20 9.8 46.41 27.5 7.64 10.3 5.5527.6 9.42 10.5 99.74 28.1 1.43 10.9 11.45 28.4 13.20 11.2 5.67 28.7 3.6411.8 5.10 28.9 5.81 13.7 24.35 29.2 5.97 14.0 9.45 29.5 2.80 14.1 59.9029.8 3.78 14.7 6.49 30.0 4.57 16.6 52.03 30.2 5.86 17.0 37.49 30.6 3.7317.3 56.50 31.1 1.64 18.0 3.30 31.6 3.62 18.3 16.05 31.9 1.07 18.7 41.4832.5 1.55 18.8 54.81 33.1 5.45 19.1 31.94 33.3 1.71 19.4 8.97 33.7 0.6619.7 25.38 34.1 2.01 20.0 4.56 34.3 2.49 20.4 7.31 35.4 1.19 20.6 11.1135.7 1.20 20.8 6.26 36.2 4.29 21.1 22.76 36.3 4.30 21.2 34.92 36.5 2.5122.1 5.75 36.9 1.70 22.3 18.70 37.1 1.30 22.5 33.36 37.5 2.10 22.8 36.3738.0 1.09 23.0 10.85 38.2 1.05 23.2 2.20 38.9 3.39 23.6 3.63 39.4 1.7324.0 9.03 24.4 9.86 24.7 3.54 24.8 3.71 25.2 32.94 25.6 20.13 25.8 21.4526.0 7.67 26.6 8.01

Example 7: Preparation of Crystalline MeCN Solvate Form I of Compound 1

The crystalline MeCN solvate Form I was prepared by slurry of compound 1in MeCN at RT for 14 days.

DSC endotherm onset of about 112° C., TGA comprising an approximate 6.9%weight loss when heated from about 38° C. to about 170° C. (1 mol MeCN).

NMR 0.9 mol MeCN.

The crystalline MeCN solvate Form I prepared above was characterized byproton NMR, X-ray powder diffraction (XRPD) data (FIG. 25), DSC (FIG.26), and TGA (FIG. 27).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.85-1.00 (m, 3H) 1.07 (d, J=6.82 Hz,3H) 1.35 (d, J=6.82 Hz, 3H) 1.90 (s, 3H) 1.99-2.16 (m, 2H) 2.52-2.78 (m,1H) 3.14 (br s, 1H) 3.35-3.56 (m, 1H) 3.57-3.84 (m, 2H) 3.86-4.09 (m,1H) 4.09-4.19 (m, 1H) 4.19-4.47 (m, 2H) 4.90 (br s, 1H) 5.66-5.80 (m,1H) 6.20 (br dd, J=16.73, 4.58 Hz, 1H) 6.61-6.76 (m, 2H) 6.78-6.94 (m,1H) 7.11-7.21 (m, 1H) 7.21-7.31 (m, 1H) 8.16-8.36 (m, 2H) 8.39 (d,J=4.69 Hz, 1H) 10.21 (br s, 1H).

TABLE 7 XRPD data of the Crystalline MeCN solvate Form I of Compound 1XRPD Peak Table: Pos. [°2Th.] Rel. Int. [%] Pos. [°2Th.] Rel. Int. [%]7.2 72.45 25.3 10.74 9.9 52.43 25.7 13.79 10.0 37.15 26.5 21.93 10.28.87 26.8 9.15 10.5 2.74 27.0 26.55 11.2 91.77 27.4 8.80 11.3 15.89 27.512.09 11.6 8.89 28.0 11.68 13.2 4.06 28.4 12.41 13.7 3.17 28.6 11.6714.2 25.71 28.8 8.71 14.5 100.00 29.1 10.79 15.7 1.02 29.7 3.00 16.615.62 30.1 3.21 16.9 66.32 30.5 13.17 17.2 2.44 30.8 5.66 17.4 4.61 31.09.44 18.0 14.01 31.2 3.79 18.2 53.02 31.9 1.38 18.7 56.63 32.2 5.20 18.949.31 32.3 7.29 19.8 3.70 33.5 2.46 20.1 21.31 34.0 1.40 20.4 16.05 34.42.91 20.8 4.63 34.9 3.17 21.0 5.42 35.2 3.57 21.7 73.71 35.4 2.40 22.35.02 36.2 0.94 22.5 5.69 36.6 2.12 22.7 34.41 37.0 4.21 23.0 6.77 37.73.05 23.4 15.57 37.9 5.41 23.6 15.11 38.0 3.75 24.1 37.36 38.5 2.87 25.08.92 38.9 3.18

Example 8: Preparation of Crystalline MEK Solvate Form I of Compound 1

The crystalline MEK solvate Form I was prepared by dissolving Compound 1in MEK at RT, polish filtering then charging with aliquots of heptane asan antisolvent until precipitation occurred. Solids were isolated afterstirring at RT for 13 days. Also prepared by slurry of amorphousCompound 1 in MEK at RT.

DSC endotherm onset of about 106° C., TGA comprising an approximate10.7% weight loss when heated from about 39° C. to about 197° C. (0.9mol MEK)

NMR 0.8 mol MEK.

The crystalline MEK solvate Form I prepared above was characterized byproton NMR, X-ray powder diffraction (XRPD) data (FIG. 28), DSC (FIG.29), and TGA (FIG. 30).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.92 (q, J=7.05 Hz, 5H) 1.08 (d, J=6.62Hz, 3H) 1.35 (d, J=6.62 Hz, 3H) 1.90 (s, 3H) 2.04-2.10 (m, 2H) 2.36-2.49(m, 2H) 2.60-2.93 (m, 1H) 3.15 (br s, 1H) 3.36-3.57 (m, 2H) 3.57-3.84(m, 4H) 3.86-4.09 (m, 2H) 4.15 (br d, J=12.82 Hz, 1H) 4.22-4.46 (m, 4H)4.91 (br s, 2H) 5.72-5.83 (m, 2H) 6.00-6.21 (m, 1H) 6.23 (br d, J=4.49Hz, 1H) 6.64-6.78 (m, 3H) 6.78-7.00 (m, 2H) 7.17-7.31 (m, 3H) 8.16-8.35(m, 1H) 8.39 (d, J=4.92 Hz, 1H) 10.22 (br s, 1H).

TABLE 8 XRPD data of the Crystalline MEK solvate Form I of Compound 1XRPD Peak Table: Pos. [°2Th.] Rel. Int. [%] Pos. [°2Th.] Rel. Int. [%]7.0 47.52 25.8 25.93 8.8 70.25 26.3 8.43 9.8 56.17 26.8 6.92 10.4 100.0027.0 2.12 10.9 22.80 27.2 3.88 11.2 11.60 27.4 8.69 11.8 9.64 27.6 7.1513.6 31.04 27.9 1.14 14.1 78.89 28.2 6.71 14.7 19.18 28.3 13.70 16.679.53 28.6 8.63 16.8 30.39 29.0 18.29 17.0 26.79 29.6 7.09 17.2 47.4830.1 14.00 17.5 3.12 30.3 2.13 18.1 5.01 30.7 3.85 18.4 23.39 31.3 3.8018.7 35.48 31.71 4.92 18.9 65.12 32.0 0.54 19.2 48.49 32.5 0.62 19.410.83 32.8 4.00 19.7 46.72 33.2 2.69 20.4 6.72 33.5 5.80 20.7 15.78 34.15.30 20.9 6.30 34.7 1.61 21.2 80.14 35.0 0.76 22.1 8.83 35.5 2.20 22.432.98 36.0 5.55 22.6 48.82 36.2 7.66 22.7 34.64 36.6 1.43 22.9 13.3337.0 0.51 23.7 9.34 37.5 3.76 24.1 18.80 38.1 1.54 24.5 27.07 38.4 1.6024.8 11.35 38.7 2.93 25.0 28.12 39.3 0.73 25.3 17.14 39.6 4.20 25.736.16

Example 9: Preparation of the Crystalline EtOAc Solvate Form I ofCompound 1

The crystalline EtOAc Solvate Form I was prepared by a slurry ofCompound 1 with ethyl acetate (EtOAc) at RT for 24 h.

The crystalline MEK solvate Form I prepared above was characterized byproton NM/R and X-ray powder diffraction (XRPD) data (FIG. 31)

TABLE 9 XRPD data of crystalline EtOAc Solvate Form I of Compound 1:XRPD Peak Table: Pos. Rel. Int. Pos. Rel. Int. Pos. Rel. Int. [°2Th.][%] [°2Th.] [%] [°2Th.] [%] 7.1 8.9 23.1 14.8 34.3 4.0 9.0 55.8 23.8 9.934.8 1.2 9.8 36.0 24.1 8.2 35.4 2.4 10.5 100.0 24.5 19.9 35.7 1.8 11.019.6 24.8 11.5 35.9 3.9 11.3 5.6 25.1 35.4 36.3 10.9 11.9 1.9 25.4 11.836.8 2.9 12.5 2.2 25.8 35.3 37.0 2.7 13.7 21.3 26.0 24.8 37.3 1.9 14.248.6 26.6 17.1 37.9 2.7 14.7 11.8 27.0 2.0 38.1 3.0 16.7 51.6 27.5 9.139.1 4.3 17.0 39.5 27.7 4.7 39.7 3.3 17.4 40.6 28.0 4.2 40.1 3.1 18.14.6 28.6 13.0 40.4 3.6 18.3 10.5 29.0 10.6 41.2 2.5 18.9 38.1 29.2 10.941.6 3.6 19.2 23.2 29.7 5.0 42.0 1.3 19.5 11.8 30.2 4.8 42.5 2.2 19.730.5 30.9 5.5 43.2 4.1 20.0 2.9 31.3 3.2 43.5 3.4 20.4 3.8 31.7 4.5 43.82.2 20.7 12.9 32.1 3.4 44.1 2.6 21.3 59.1 32.6 1.8 44.4 2.3 22.1 3.733.1 6.8 22.6 30.7 33.6 5.2 22.8 34.2 34.0 2.9

Example 10: Preparation of the DMF Solvate Form I of Compound 1

The crystalline DMF solvate Form I of Compound 1 was prepared by aslurry of Compound 1 in DMF/water at RT for 24 h.

The crystalline DMF solvate Form I of Compound 1 prepared above wascharacterized by proton NMR, X-ray powder diffraction (XRPD) data (FIG.32), DSC (FIG. 33), and TGA (FIG. 34).

DSC endotherm onset of about 74° C., TGA comprising an approximate 17%weight loss when heated from about 36° C. to about 195° C.

NMR 1-2 mol DMF.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.94 (d, J=6.49 Hz, 4H) 1.08 (d, J=6.75Hz, 4H) 1.35 (d, J=6.75 Hz, 4H) 1.91 (s, 4H) 2.30 (s, 1H) 2.55 (t,J=5.58 Hz, 1H) 2.73 (s, 6H) 2.89 (s, 5H) 3.00-3.21 (m, 1H) 3.27 (br d,J=13.49 Hz, 2H) 3.34 (br s, 5H) 3.60-3.74 (m, 2H) 3.96-4.16 (m, 1H) 4.32(br d, J=13.75 Hz, 2H) 4.39 (br s, 1H) 4.90 (br s, 1H) 5.67-5.86 (m, 1H)6.20 (br dd, J=16.61, 7.27 Hz, 1H) 6.64-6.77 (m, 2H) 6.79-6.92 (m, 1H)7.17-7.32 (m, 2H) 7.95 (s, 1H) 8.28 (br dd, J=16.22, 9.21 Hz, 1H) 8.40(d, J=4.93 Hz, 1H) 10.19 (d, J=1.30 Hz, 1H).

TABLE 10 XRPD data of the Crystalline DMF Solvate Form I of Compound 1XRPD Peak Table: Pos. [°2Th.] Rel. Int. [%] Pos. [°2Th.] Rel. Int. [%]7.8 100.0 24.3 12.6 8.1 60.0 24.9 11.5 9.0 19.1 25.4 12.7 12.4 17.5 26.817.8 13.3 7.5 27.3 11.1 14.4 25.9 28.3 30.4 15.0 7.4 28.6 38.6 16.1 11.429.4 12.3 16.8 26.5 30.4 6.0 17.3 17.5 31.6 6.2 18.9 12.3 34.0 3.3 19.958.6 35.7 1.9 20.8 38.6 37.9 2.6 21.8 11.0 42.2 2.2 23.3 17.0

Example 11: Preparation of the Crystalline DCM Solvate Form I ofCompound 1

The crystalline DCM solvate Form I of Compound 1 was prepared bydissolving Compound 1 in DCM at RT, polish filtering, then charging thealiquots of heptane as an antisolvent until precipitation occurred.Solids were isolated after stirring at RT for 1 h.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.84-1.02 (m, 2H) 1.07 (d, J=6.61 Hz,2H) 1.35 (d, J=6.82 Hz, 2H) 1.90 (s, 2H) 2.64-2.80 (m, 1H) 3.14 (br t,J=11.19 Hz, 1H) 3.45-3.57 (m, 1H) 3.58-3.84 (m, 2H) 3.86-4.09 (m, 1H)4.09-4.21 (m, 1H) 4.21-4.46 (m, 2H) 4.90 (br s, 1H) 5.65-5.86 (m, 2H)6.08-6.28 (m, 1H) 6.63-6.76 (m, 2H) 6.86 (dt, J=16.46, 11.27 Hz, 1H)7.12-7.21 (m, 1H) 7.21-7.31 (m, 1H) 8.16-8.36 (m, 2H) 8.39 (d, J=4.90Hz, 1H) 10.20 (br s, 1H).

The crystalline DCM solvate Form I of Compound 1 prepared above wascharacterized by proton NMR, X-ray powder diffraction (XRPD) data (FIG.35), DSC (FIG. 36), and TGA (FIG. 37).

DSC endotherm onset of about 174° C., TGA comprising an approximate 7.2%weight loss when heated from about 40° C. to about 200° C. (0.5 mol DCM)from 40-200°.

NMR 0.5 mol DCM

TABLE 11 XRPD data of the Crystalline DCM Solvate Form I of Compound 1XRPD Peak Table Pos. Rel. Int. Pos. Rel. Int. Pos. Rel. Int. [°2Th.] [%][°2Th.] [%] [°2Th.] [%] 7.1 53.6 21.3 16.8 29.3 9.3 9.5 100.0 21.4 65.329.5 5.3 10.1 64.3 21.8 33.6 29.9 6.6 10.9 95.6 22.8 74.2 30.1 8.7 11.79.1 23.2 12.1 30.4 17.3 11.6 3.4 23.5 23.7 30.8 6.6 13.8 12.2 23.6 43.131.3 3.7 14.0 26.5 23.9 10.5 31.7 4.0 14.3 95.5 24.4 11.9 32.3 7.2 14.612.7 25.0 17.6 32.5 7.7 15.2 7.2 25.2 12.8 33.0 2.4 16.6 23.7 25.8 21.933.5 1.9 16.8 97.7 26.2 58.2 34.2 8.3 17.6 36.1 26.5 18.3 34.8 2.8 17.886.9 26.7 19.1 35.7 2.3 18.6 35.9 27.2 14.4 36.9 2.4 18.9 65.9 27.3 13.437.3 6.5 19.1 88.3 27.7 14.8 37.8 9.6 19.8 6.0 28.0 14.5 38.8 2.4 20.231.9 28.3 22.0 39.1 3.6 20.7 16.3 28.7 12.6 21.0 13.2 29.0 9.0

Example 12: Preparation of the Crystalline Acetone Solvate Form I ofCompound 1

The crystalline acetone solvate Form I of Compound 1 was prepared by aslurry of amorphous Compound 1 in acetone/water (50:50) at RT or aslurry of Compound 1 in acetone/water (50:50) at 2-8° C. for 15 days.

The crystalline acetone solvate Form I of Compound 1 prepared above wascharacterized by proton NMR, X-ray powder diffraction (XRPD) data (FIG.38), DSC (FIG. 39), and TGA (FIG. 40).

DSC endotherm onset of about 72° C., TGA comprising an approximate 21.4%weight loss when heated from about 38° C. to about 130° C. (0.7 molacetone and 5.3 mol water).

NMR 0.7 mol acetone.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.84-1.00 (m, 3H) 1.07 (d, J=6.61 Hz,3H) 1.34 (d, J=6.61 Hz, 3H) 1.90 (s, 3H) 2.05-2.12 (m, 3H) 2.52-2.78 (m,2H) 3.08-3.21 (m, 1H) 3.45-3.57 (m, 1H) 3.67 (br d, J=11.72 Hz, 2H)3.97-4.06 (m, 1H) 4.08-4.21 (m, 1H) 4.32 (br d, J=13.85 Hz, 2H) 4.90 (brs, 1H) 5.54-5.80 (m, 2H) 5.99-6.26 (m, 2H) 6.52-6.75 (m, 2H) 6.84 (br s,1H) 7.09-7.30 (m, 2H) 8.12-8.36 (m, 3H) 8.38 (d, J=4.90 Hz, 1H) 10.21(br s, 1H).

TABLE 12 XRPD data of the Crystalline Acetone Solvate Form I of Compound1 XRPD Peak Table Pos. [°2Th.] Rel. Int. [%] Pos. [°2Th.] Rel. Int. [%]5.6 1.4 24.0 17.6 7.8 100.0 24.7 11.9 8.1 38.3 25.0 10.8 9.0 13.1 25.615.7 11.2 2.3 26.1 11.1 12.4 22.1 26.6 10.6 12.6 4.9 26.9 22.9 13.2 36.527.1 17.5 14.3 78.7 27.8 5.7 14.9 10.7 28.1 22.0 15.0 10.1 28.4 8.6 15.74.7 28.8 16.2 16.4 20.2 29.1 13.0 16.6 7.7 29.4 10.9 16.8 12.4 30.2 13.516.9 19.6 30.9 6.5 17.0 9.4 31.3 7.7 17.3 11.5 31.6 7.3 17.5 10.8 31.95.6 18.0 2.1 32.6 4.9 18.8 26.4 33.2 2.9 19.8 16.6 33.6 7.3 20.1 32.634.5 6.2 20.2 24.2 35.0 3.8 20.5 37.7 35.4 3.7 20.7 17.3 35.8 3.3 21.45.0 36.6 2.9 21.6 14.4 36.9 3.8 22.6 2.7 37.3 5.3 23.1 4.1 37.8 4.0 23.26.4 38.7 4.5 23.4 7.3 39.3 3.2 23.9 12.0

Example 13: Preparation of the Crystalline Acetone Solvate Form II ofCompound 1

The crystalline acetone solvate Form II of Compound 1 was prepared by aslurry Compound 1 in acetone at 2-8° C. for 15 days.

The crystalline acetone solvate Form II of Compound 1 prepared above wascharacterized by proton NMR, X-ray powder diffraction (XRPD) data (FIG.41), DSC (FIG. 42), and TGA (FIG. 43).

DSC endotherm onset of about 137° C., TGA comprising an approximate 7.3%weight loss when heated from about 100° C. to about 200° C. (0.8 molacetone).

NMR 0.7 mol acetone

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.83-1.02 (m, 3H) 1.07 (d, J=6.82 Hz,2H) 1.35 (d, J=6.61 Hz, 2H) 1.90 (s, 2H) 2.09 (s, 3H) 2.52-2.77 (m, 1H)3.18 (br s, 1H) 3.45-3.57 (m, 1H) 3.66 (br s, 4H) 3.96-4.08 (m, 1H)4.08-4.20 (m, 1H) 4.32 (br d, J=13.64 Hz, 3H) 4.90 (br s, 2H) 5.69-5.80(m, 1H) 6.15-6.26 (m, 1H) 6.60-6.75 (m, 2H) 6.79-6.94 (m, 1H) 7.07-7.21(m, 1H) 7.27 (td, J=8.31, 7.03 Hz, 1H) 8.20-8.36 (m, 2H) 8.39 (d, J=4.90Hz, 1H) 10.20 (br s, 1H).

TABLE 13 XRPD data of the Crystalline Acetone Solvate Form II ofCompound 1 XRPD Peak Table Pos. [°2Th.] Rel. Int. [%] Pos. [°2Th.] Rel.Int. [%] 7.1 60.1 25.5 17.5 9.1 38.0 25.8 29.5 9.9 47.8 26.1 13.0 10.315.8 26.8 4.9 10.6 56.1 27.0 12.0 10.9 13.4 27.3 4.9 11.3 15.8 27.8 13.611.8 8.7 28.2 9.8 12.7 1.1 28.6 12.5 13.8 27.0 28.8 5.9 14.0 17.3 29.211.7 14.2 59.6 29.5 4.8 14.7 13.0 29.7 5.9 16.7 60.7 29.9 3.7 16.9 26.630.3 7.0 17.1 14.3 30.7 7.2 17.4 29.3 30.7 4.2 17.7 7.9 31.4 5.2 18.212.6 31.7 6.6 18.5 17.5 32.0 4.5 18.7 33.6 33.1 2.9 19.0 100.0 33.3 7.619.6 4.7 34.3 4.9 19.9 32.0 35.4 0.8 20.3 3.3 35.7 2.3 20.8 29.1 36.21.7 21.3 46.3 36.5 6.2 22.3 37.3 37.0 2.4 22.7 50.5 37.4 1.0 23.0 32.637.7 2.8 23.7 5.9 37.9 4.2 24.1 16.5 38.6 2.1 24.6 17.2 39.1 2.8 24.95.0 39.7 3.8 25.3 18.9

Example 14: Preparation of the Crystalline P-Dioxane Solvate Form I ofCompound 1

The crystalline p-dioxane solvate Form I of Compound 1 was prepared by aslurry of Compound 1 in p-dioxane at RT for 14 days.

The crystalline p-dioxane solvate Form I of Compound 1 prepared abovewas characterized by proton NMR, X-ray powder diffraction (XRPD) data(FIG. 44), DSC (FIG. 45), and TGA (FIG. 46).

DSC endotherm onset of about 112° C., TGA comprising an approximate23.2% weight loss when heated from about 25° C. to about 150° C. (1.9mol p-dioxane)

NMR 1.9 mol p-dioxane

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.84-1.00 (m, 3H) 1.07 (d, J=6.61 Hz,3H) 1.35 (d, J=6.82 Hz, 3H) 1.90 (s, 2H) 2.52-2.77 (m, 2H) 3.05-3.28 (m,1H) 3.32 (s, 4H) 3.58-3.78 (m, 3H) 3.98-4.07 (m, 1H) 4.09-4.20 (m, 1H)4.09-4.19 (m, 1H) 4.15-4.43 (m, 1H) 4.16-4.21 (m, 1H) 4.22-4.45 (m, 1H)4.23-4.45 (m, 1H) 4.90 (br s, 1H) 5.61-5.80 (m, 1H) 6.20 (br dd,J=16.62, 4.48 Hz, 1H) 6.58-6.76 (m, 2H) 6.79-6.93 (m, 1H) 7.10-7.21 (m,1H) 7.21-7.31 (m, 1H) 8.14-8.36 (m, 3H) 8.39 (d, J=4.90 Hz, 1H) 10.20(br s, 1H)

TABLE 14 XRPD data of the Crystalline p-Dioxane Solvate Form I ofCompound 1 XRPD Peak Table Pos. [°2Th.] Rel. Int. [%] Pos. [°2Th.] Rel.Int. [%] 7.8 94.7 24.1 55.3 9.5 83.9 24.3 8.5 9.6 55.6 25.0 25.5 10.27.1 25.9 21.9 11.0 59.4 26.6 26.6 11.3 30.2 27.0 20.1 11.8 1.0 27.3 7.112.9 71.9 27.4 9.2 13.2 1.6 27.7 10.6 13.7 6.4 28.0 6.4 14.3 13.0 28.15.0 15.8 81.2 28.6 20.8 16.4 4.8 28.8 6.5 16.6 4.5 29.1 6.3 17.7 81.529.2 5.9 18.1 49.0 29.6 6.6 18.3 40.0 30.0 7.1 18.6 85.4 30.4 4.6 18.8100.0 30.5 8.0 19.0 63.4 31.0 12.2 19.2 94.1 31.5 3.3 19.8 88.2 32.0 8.620.0 73.8 32.3 5.4 20.4 13.1 32.7 1.2 20.5 42.2 33.3 9.4 20.9 13.0 34.33.1 21.2 41.5 34.9 4.0 21.6 22.5 35.5 4.3 21.7 20.6 35.9 5.3 22.0 34.736.3 1.1 22.4 6.1 36.8 2.8 22.7 8.0 37.0 5.2 23.0 3.2 37.4 1.0 23.3 14.637.8 1.7 23.6 32.9 38.9 3.1 23.7 47.2 39.5 3.6

Example 15: Preparation of the Crystalline Methanol Solvate Form I ofCompound 1

The crystalline methanol (MeOH) solvate Form I of Compound 1 wasprepared by placing Compound 1 in a small open vial then placing thisvial inside a larger vial containing MeOH and capped to vapor stress thesolids at RT for 4 days.

The crystalline MeOH Solvate Form I of Compound 1 prepared above wascharacterized by proton NMR, X-ray powder diffraction (XRPD) data (FIG.47), DSC (FIG. 48), and TGA (FIG. 49).

DSC endotherm onset of about 57° C., TGA comprising an approximate 5.2%weight loss when heated from about 38° C. to about 220° C. (1.0 molMeOH)

NMR 0.8 mol MeOH

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.94 (d, J=6.62 Hz, 3H) 1.08 (d, J=6.62Hz, 3H) 1.35 (d, J=6.84 Hz, 3H) 1.90 (s, 3H) 2.64-2.80 (m, 1H) 3.18 (d,J=4.92 Hz, 3H) 3.48-3.76 (m, 2H) 3.97-4.21 (m, 2H) 4.21-4.47 (m, 2H)4.91 (br s, 1H) 5.69-5.86 (m, 1H) 6.21 (br dd, J=16.67, 4.49 Hz, 1H)6.63-6.79 (m, 2H) 6.80-6.98 (m, 1H) 7.17-7.31 (m, 2H) 8.18-8.35 (m, 1H)8.39 (d, J=4.92 Hz, 1H) 10.22 (br s, 1H)

TABLE 15 XRPD data of the Crystalline MeOH Solvate Form I of Compound 1XRPD Peak Table Pos. [°2Th.] Rel. Int. [%] Pos. [°2Th.] Rel. Int. [%]7.2 22.9 26.3 21.1 9.0 30.8 26.8 12.1 9.7 42.7 27.5 5.2 10.3 13.3 27.84.5 10.6 100.0 28.1 3.8 11.2 44.1 28.5 7.3 12.1 4.1 28.7 15.9 13.7 26.429.0 9.4 14.1 10.9 29.2 7.1 14.4 91.4 29.9 6.5 14.9 43.3 30.3 3.7 16.00.9 31.1 3.3 16.8 91.1 31.4 10.8 17.0 18.4 31.5 9.2 17.2 5.0 32.2 1.417.4 37.0 32.4 1.3 17.6 15.5 33.4 1.3 17.8 22.7 33.6 1.7 18.1 8.0 33.82.2 18.7 35.3 34.1 1.6 18.9 4.5 34.4 3.6 19.1 3.6 34.9 3.1 19.5 74.734.9 3.9 20.0 1.7 35.5 1.8 20.3 1.6 35.7 2.4 20.6 4.7 36.1 1.7 21.1 21.936.7 5.1 21.3 2.9 37.3 1.9 21.7 68.4 37.9 2.2 22.0 5.9 38.1 2.8 22.517.1 38.8 1.6 22.7 9.7 39.7 2.6 23.0 17.7 39.9 3.0 23.3 4.1 24.2 8.224.3 12.9 24.6 40.5 25.1 22.7 25.4 5.6 25.9 35.7

Example 16: Preparation of the Crystalline IPA Solvate Form I ofCompound 1

The crystalline isopropanol (IPA) solvate Form I of Compound 1 wasprepared by slurry of amorphous Compound 1 in IPA at RT for 5 days.

The crystalline IPA solvate Form I of Compound 1 prepared above wascharacterized by proton NMR, X-ray powder diffraction (XRPD) data (FIG.50), DSC (FIG. 51), and TGA (FIG. 52).

DSC endotherm onset of about 56° C., TGA comprising an approximate 8.7%weight loss when heated from about 39° C. to about 190° C. (0.9 mol IPA)

NMR 2.3 mol IPA

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.94 (d, J=6.62 Hz, 3H) 1.02-1.06 (m,1H) 1.05 (d, J=5.98 Hz, 14H) 1.35 (d, J=6.62 Hz, 3H) 1.90 (s, 3H) 2.72(br s, 1H) 3.10-3.21 (m, 1H) 3.45-3.58 (m, 1H) 3.78 (td, J=6.09, 4.06Hz, 9H) 3.98-4.09 (m, 1H) 4.16 (br s, 1H) 4.35 (d, J=4.06 Hz, 8H) 4.91(br d, J=0.85 Hz, 1H) 5.73-5.83 (m, 2H) 6.16-6.28 (m, 1H) 6.66-6.93 (m,5H) 7.19 (dd, J=4.81, 0.75 Hz, 2H) 7.23-7.33 (m, 2H) 8.39 (d, J=4.92 Hz,3H) 10.21 (br s, 1H).

TABLE 16 XRPD data of the Crystalline MeOH Solvate Form I of Compound 1XRPD Peak Table: Pos. [°2Th.] Rel. Int. [%] Pos. [°2Th.] Rel. Int. [%]7.1 84.1 26.6 5.6 9.2 73.8 27.0 11.0 9.8 47.9 27.7 15.1 10.2 4.2 27.88.3 10.6 89.1 28.2 8.7 11.2 17.2 28.5 10.5 11.7 5.1 28.7 18.2 13.7 38.929.0 2.9 14.1 82.0 29.3 2.6 14.6 7.5 29.5 6.7 14.8 1.8 29.9 9.8 16.690.0 30.2 6.2 16.8 30.3 30.4 7.9 17.2 20.0 30.9 4.5 17.5 52.1 31.2 5.018.0 23.3 31.7 4.2 18.2 15.9 31.8 4.8 18.6 38.1 32.7 3.4 18.8 100.0 32.96.2 18.9 75.5 33.0 5.8 19.2 10.6 33.5 6.0 19.7 52.3 34.1 5.5 20.4 27.034.7 2.3 21.0 21.5 35.2 3.0 21.3 65.6 35.5 0.8 22.0 28.6 35.9 2.1 22.214.3 36.2 2.5 22.5 50.5 36.5 4.4 22.9 19.9 36.6 3.5 23.1 27.1 36.9 2.723.3 8.6 37.0 2.6 23.5 8.8 37.4 5.7 23.8 11.3 38.1 1.2 24.2 19.0 38.31.0 24.8 12.0 38.7 1.2 25.0 16.1 39.1 4.9 25.4 37.9 39.5 2.1 25.5 45.326.1 16.0

Example 17: Preparation of the Crystalline EtOH Solvate Form I ofCompound 1

The crystalline ethanol (EtOH) solvate Form I of Compound 1 was preparedby slurry of amorphous Compound 1 in EtOH at RT for 10 days.

The crystalline EtOH solvate Form I of Compound 1 prepared above wascharacterized by proton NMR, X-ray powder diffraction (XRPD) data (FIG.53), DSC (FIG. 54), and TGA (FIG. 55).

DSC endotherm onset of about 194° C., TGA comprising an approximate 5%weight loss when heated from about 36° C. to about 195° C. (0.6 molEtOH)

NMR 0.7 mol EtOH.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.84-1.02 (m, 5H) 1.02-1.12 (m, 5H) 1.35(d, J=6.82 Hz, 3H) 1.90 (s, 3H) 2.52-2.77 (m, 1H) 3.14 (br t, J=10.87Hz, 1H) 3.34-3.57 (m, 2H) 3.58-3.84 (m, 2H) 3.86-4.08 (m, 1H) 4.09-4.21(m, 1H) 4.21-4.46 (m, 3H) 4.90 (br s, 1H) 5.51-5.80 (m, 1H) 6.20 (br dd,J=16.52, 4.58 Hz, 1H) 6.62-6.75 (m, 2H) 6.86 (dt, J=16.30, 11.24 Hz, 1H)7.13-7.19 (m, 1H) 7.27 (td, J=8.20, 7.03 Hz, 1H) 8.16-8.36 (m, 2H) 8.39(d, J=4.90 Hz, 1H) 10.20 (br s, 1H).

TABLE 17 XRPD data of the Crystalline EtOH Solvate Form I of Compound 1XRPD Peak Table: Pos. [°2Th.] Rel. Int. [%] Pos. [°2Th.] Rel. Int. [%]7.2 63.3 25.6 27.2 9.3 42.8 25.7 24.1 9.8 35.9 26.2 5.4 10.2 6.1 26.514.6 10.8 100.0 27.3 8.6 11.2 13.4 27.8 8.2 11.9 5.3 28.7 11.6 12.7 0.929.0 7.1 13.8 28.1 29.3 1.6 14.4 91.3 29.9 4.9 14.7 14.3 30.3 1.8 16.877.0 30.5 3.0 17.1 21.3 31.0 6.1 17.3 19.5 31.3 2.3 17.8 34.9 31.8 2.117.9 14.9 32.3 1.7 18.2 3.0 32.7 0.1 18.8 40.0 33.5 2.4 19.1 31.5 34.14.1 19.7 25.4 34.7 1.7 20.5 8.9 35.0 1.6 20.8 3.3 35.7 1.1 21.0 8.2 36.51.3 21.6 54.2 37.1 4.8 22.6 26.1 38.0 3.2 23.0 9.5 39.5 1.4 23.4 16.639.8 1.8 23.9 7.1 24.4 11.8 24.9 11.5

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the disclosure.It is intended, therefore, that the invention be defined by the scope ofthe claims that follow and that such claims be interpreted as broadly asis reasonable.

What is claimed is:
 1. A compound, wherein the compound is a crystallineform of6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one(Compound 1) or an atropisomer thereof.
 2. The compound of claim 1,wherein the compound is the M atropisomer of Compound
 1. 3. The compoundof claim 1 or 2, wherein the compound is a crystalline anhydrous form ofCompound
 1. 4. The compound of any one of claims 1-3, wherein thecompound is characterized by a powder X-ray diffraction patterncomprising peaks at 9.0, 12.0, 12.6, and 19.0±0.2 degrees 2 theta asmeasured by x-ray powder diffraction using an x-ray wavelength of 1.54Å.
 5. The compound of any one of claims 1-3, wherein the compound ischaracterized by a powder X-ray diffraction pattern comprising at leastthree peaks selected from 8.8, 9.0, 10.8, 12.0, 12.6, 12.8, 13.6, 14.2,15.0, 15.4, 18.0, 18.6, 18.7, 19.0, 19.9, 20.0, 22.9, and 25.0±0.2degrees 2 theta as measured by x-ray powder diffraction using an x-raywavelength of 1.54 Å.
 6. The compound of any one of claims 1-3, whereinthe compound is characterized by a powder X-ray diffraction patterncomprising at least five peaks selected from 8.8, 9.0, 10.8, 12.0, 12.6,12.8, 13.6, 14.2, 15.0, 15.4, 18.0, 18.6, 18.7, 19.0, 19.9, 20.0, 22.9,and 25.0±0.2 degrees 2 theta as measured by x-ray powder diffractionusing an x-ray wavelength of 1.54 Å.
 7. The compound of any one ofclaims 1-3, wherein the compound is characterized by a powder X-raydiffraction pattern comprising at least seven peaks selected from 8.8,9.0, 10.8, 12.0, 12.6, 12.8, 13.6, 14.2, 15.0, 15.4, 18.0, 18.6, 18.7,19.0, 19.9, 20.0, 22.9, and 25.0±0.2 degrees 2 theta as measured byx-ray powder diffraction using an x-ray wavelength of 1.54 Å.
 8. Thecompound of any one of claims 1-3, wherein the compound is characterizedby a powder X-ray diffraction pattern comprising peaks at 8.8, 9.0,10.8, 12.0, 12.6, 12.8, 13.6, 14.2, 15.0, 15.4, 18.0, 18.6, 18.7, 19.0,19.9, 20.0, 22.9, and 25.0±0.2 degrees 2 theta as measured by x-raypowder diffraction using an x-ray wavelength of 1.54 Å.
 9. The compoundof any one of claims 1-3, wherein the compound is characterized by thepowder X-ray diffraction pattern substantially as shown in FIG. 5 asmeasured by x-ray powder diffraction using an x-ray wavelength of 1.54Å.
 10. The compound of any one of claims 1-9, wherein the compound ischaracterized by a differential scanning calorimetry thermogramcomprising an endotherm with an onset of about 293° C.
 11. The compoundof any one of claims 1-10, wherein the compound is characterized by athermogravimetric analysis thermogram comprising a weight loss of about0.2% when heated from about 25° C. to about 275° C.
 12. The compound ofany one of claims 1-11, wherein the compound is characterized by ¹³Csolid state NMR comprising at least three peaks selected from peaks atapproximately 12, 13, 16, 21, 23, 31, 33, 38, 42, 44, 47, 50, 54, 107,110, 111, 123, 124, 127, 128, 132, 145, 146, 150, 154, 156, 158, 160,162, 166, 167, and 168 ppm.
 13. The compound of any one of claims 1-11,wherein the compound is characterized by ¹³C solid state NMR comprisingat least five peaks selected from peaks at approximately 12, 13, 16, 21,23, 31, 33, 38, 42, 44, 47, 50, 54, 107, 110, 111, 123, 124, 127, 128,132, 145, 146, 150, 154, 156, 158, 160, 162, 166, 167, and 168 ppm. 14.The compound of any one of claims 1-11, wherein the compound ischaracterized by ¹³C solid state NMR comprising at least seven peaksselected from peaks at approximately 12, 13, 16, 21, 23, 31, 33, 38, 42,44, 47, 50, 54, 107, 110, 111, 123, 124, 127, 128, 132, 145, 146, 150,154, 156, 158, 160, 162, 166, 167, and 168 ppm.
 15. The compound of anyone of claims 1-11, wherein the compound is characterized by ¹³C solidstate NMR comprising peaks at approximately 12, 13, 16, 21, 23, 31, 33,38, 42, 44, 47, 50, 54, 107, 110, 111, 123, 124, 127, 128, 132, 145,146, 150, 154, 156, 158, 160, 162, 166, 167, and 168 ppm.
 16. Thecompound of any one of claims 1-11, wherein the compound ischaracterized by ¹³C solid state NMR substantially as depicted in FIG. 8as measured by x-ray powder diffraction using an x-ray wavelength of1.54 Å.
 17. The compound of any one of claims 1-16, wherein the compoundis characterized by ¹⁹F solid state NMR comprising peaks atapproximately −49, −60, −79, −90, −109, −120, −138, −150, −168, and −179ppm.
 18. The compound of any one of claims 1-16, wherein the compound ischaracterized by ¹⁹F solid state NMR substantially as depicted in FIG. 9as measured by x-ray powder diffraction using an x-ray wavelength of1.54 Å.
 19. The compound of any one of claims 1-18, wherein the compoundis substantially pure.
 20. A pharmaceutical composition comprising thecompound of any one of claims 1-19 and a pharmaceutically acceptableexcipient.
 21. The pharmaceutical composition of claim 20, wherein thepharmaceutical composition is a dosage form for oral administration. 22.The pharmaceutical composition of claim 20 or 21, wherein the dosageform is a solid dosage form.
 23. The pharmaceutical composition of claim22, wherein the solid dosage form is a tablet.
 24. The pharmaceuticalcomposition of any one of claims 20-23, wherein the pharmaceuticalcomposition comprises 120 mg of the compound.
 25. A compound of any oneof claims 1-19 or the pharmaceutical composition of any one of claims20-24 for use as a medicament.
 26. A compound of any one of claims 1-19or the pharmaceutical composition of any one of claims 20-24 for use intreating cancer having a KRAS G12C mutation.
 27. The compound or thepharmaceutical composition for use of claim 26, wherein the cancerhaving a KRAS G12C mutation is lung cancer, pancreatic cancer, orcolorectal cancer.
 28. The compound or the pharmaceutical compositionfor use of claim 26, wherein the cancer having a KRAS G12C mutation isnon-small cell lung cancer.
 29. The compound or the pharmaceuticalcomposition for use of claim 26, wherein the cancer having a KRAS G12Cmutation is pancreatic cancer.
 30. The compound or the pharmaceuticalcomposition for use of claim 26, wherein the cancer having a KRAS G12Cmutation is colorectal cancer.
 31. Use of the compound of any one ofclaims 1-19 or the pharmaceutical composition of any one of claims 20-24in the preparation of a medicament for treating cancer having a KRASG12C mutation.
 32. The use of claim 31, wherein the cancer having a KRASG12C mutation is lung cancer, pancreatic cancer, or colorectal cancer.33. The use of claim 31, wherein the cancer having a KRAS G12C mutationis non-small cell lung cancer.
 34. The use of claim 31, wherein thecancer having a KRAS G12C mutation is pancreatic cancer.
 35. The use ofclaim 31, wherein the cancer having a KRAS G12C mutation is colorectalcancer.
 36. A method of treating a cancer having a KRAS G12C mutation ina patient in need thereof, the method comprising administering to thepatient a therapeutically effective amount of the compound of any one ofclaims 1-19.
 37. The method of claim 36, wherein the cancer having aKRAS G12C mutation is lung cancer, pancreatic cancer, or colorectalcancer.
 38. The method of claim 36, wherein the cancer having a KRASG12C mutation is small cell lung cancer.
 39. The method of claim 36,wherein the cancer having a KRAS G12C mutation is pancreatic cancer. 40.The method of claim 36, wherein the cancer having a KRAS G12C mutationis colorectal cancer.
 41. The compound, use, or method of any one ofclaims 25-40, wherein the compound is administered at a total daily doseof 960 mg.
 42. The compound, use, or method of any one of claims 25-41,wherein the compound is administered to an adult.
 43. The compound ofany one of claims 1-3, wherein the compound is characterized by a powderX-ray diffraction pattern comprising peaks at 7.3, 9.8, 10.1, 11.3,13.3, and 17.2±0.2 degrees 2 theta as measured by x-ray powderdiffraction using an x-ray wavelength of 1.54 Å.
 44. The compound of anyone of claims 1-3, wherein the compound is characterized by a powderX-ray diffraction pattern comprising at least three peaks selected from7.3, 9.8, 10.1, 10.4, 11.3, 11.5, 11.9, 13.3, 14.3, 14.7, 17.2, and18.4±0.2 degrees 2 theta as measured by x-ray powder diffraction usingan x-ray wavelength of 1.54 Å.
 45. The compound of any one of claims1-3, wherein the compound is characterized by a powder X-ray diffractionpattern comprising at least five peaks selected from 7.3, 9.8, 10.1,10.4, 11.3, 11.5, 11.9, 13.3, 14.3, 14.7, 17.2, and 18.4±0.2 degrees 2theta as measured by x-ray powder diffraction using an x-ray wavelengthof 1.54 Å.
 46. The compound of any one of claims 1-3, wherein thecompound is characterized by a powder X-ray diffraction patterncomprising at least seven peaks selected from 7.3, 9.8, 10.1, 10.4,11.3, 11.5, 11.9, 13.3, 14.3, 14.7, 17.2, and 18.4±0.2 degrees 2 thetaas measured by x-ray powder diffraction using an x-ray wavelength of1.54 Å.
 47. The compound of any one of claims 1-3, wherein the compoundis characterized by a powder X-ray diffraction pattern comprising peaksat 7.3, 9.8, 10.1, 10.4, 11.3, 11.5, 11.9, 13.3, 14.3, 14.7, 17.2, and18.4±0.2 degrees 2 theta as measured by x-ray powder diffraction usingan x-ray wavelength of 1.54 Å.
 48. The compound of any one of claims1-3, wherein the compound is characterized by the powder X-raydiffraction pattern substantially as shown in FIG. 10 as measured byx-ray powder diffraction using an x-ray wavelength of 1.54 Å.
 49. Thecompound of any one of claims 1-3 and 43-48, wherein the compound ischaracterized by a differential scanning calorimetry thermogramcomprising an endotherm with an onset of about 193° C.
 50. The compoundof any one of claims 1-3 and 43-49, wherein the compound ischaracterized by having a thermogravimetric analysis thermogramcomprising a weight loss of about 1% to about 1.8% when heated fromabout 25° C. to about 250° C.
 51. The compound of any one of claims 1-3and 43-50, wherein the compound is characterized by ¹³C solid state NMRcomprising peaks at approximately 16, 18, 19, 20, 23, 25, 31, 32, 38,40, 43, 46, 51, 57, 105, 107, 110, 117, 120, 123, 124, 125, 128, 132,149, 152, 155, 158, 159, 163, and 166 ppm.
 52. The compound of any oneof claims 1-3 and 43-50, wherein the compound is characterized by ¹³Csolid state NMR substantially as depicted in FIG.
 13. 53. The compoundof any one of claims 1-3 and 43-52, wherein the compound ischaracterized by ¹⁹F solid state NMR, comprising peaks at approximately−59, −62, −89, −92, −119, −122, −148, −151, −179 and −181 ppm.
 54. Thecompound of any one of claims 1-3 and 43-52, wherein the compound ischaracterized by ¹⁹F solid state NMR substantially as depicted in FIG.14.
 55. The compound of any one of claims 43-54, wherein the compound issubstantially pure.
 56. A pharmaceutical composition comprising thecompound of any one of claims 43-55 and a pharmaceutically acceptableexcipient.
 57. The compound of any one of claims 1-3, wherein thecompound is characterized by a powder X-ray diffraction patterncomprising peaks at 6.3, 8.4, 9.5, and 16.0±0.2 degrees 2 theta asmeasured by x-ray powder diffraction using an x-ray wavelength of 1.54Å.
 58. The compound of any one of claims 1-3, wherein the compound ischaracterized by a powder X-ray diffraction pattern comprising at leastthree peaks selected from 6.3, 8.4, 9.5, 10.4, 14.9, 15.4, 15.5, 16.0,and 17.6±0.2 degrees 2 theta as measured by x-ray powder diffractionusing an x-ray wavelength of 1.54 Å.
 59. The compound of any one ofclaims 1-3, wherein the compound is characterized by a powder X-raydiffraction pattern comprising at least five peaks selected from 6.3,8.4, 9.5, 10.4, 14.9, 15.4, 15.5, 16.0, and 17.6±0.2 degrees 2 theta asmeasured by x-ray powder diffraction using an x-ray wavelength of 1.54Å.
 60. The compound of any one of claims 1-3, wherein the compound ischaracterized by a powder X-ray diffraction pattern comprising at leastseven peaks selected from 6.3, 8.4, 9.5, 10.4, 14.9, 15.4, 15.5, 16.0,and 17.6±0.2 degrees 2 theta as measured by x-ray powder diffractionusing an x-ray wavelength of 1.54 Å.
 61. The compound of any one ofclaims 1-3, wherein the compound is characterized by a powder X-raydiffraction pattern comprising peaks at 6.3, 8.4, 9.5, 10.4, 14.9, 15.4,15.5, 16.0, and 17.6±0.2 degrees 2 theta as measured by x-ray powderdiffraction using an x-ray wavelength of 1.54 Å.
 62. The compound of anyone of claims 1-3, wherein the compound is characterized by the powderX-ray diffraction pattern substantially as shown in FIG. 15 as measuredby x-ray powder diffraction using an x-ray wavelength of 1.54 Å.
 63. Thecompound of any one of claims 1-3 and 57-62, wherein the compound ischaracterized by a differential scanning calorimetry thermogramcomprising an endotherm with an onset of about 194° C.
 64. The compoundof any one of claims 1-3 and 57-63, wherein the compound ischaracterized by having an approximate negligible weight loss whenheated from about 25° C. to about 250° C.
 65. The compound of any one ofclaims 57-64, wherein the compound is substantially pure.
 66. Apharmaceutical composition comprising the compound of any one of claims57-65 and a pharmaceutically acceptable excipient.
 67. The compound ofclaim 1 or 2, wherein the compound is a crystalline hydrate form ofCompound
 1. 68. The compound of any one of claims 1, 2, and 67, whereinthe compound is characterized by a powder X-ray diffraction patterncomprising peaks at 6.9, 8.0, 9.6, 12.4, and 13.1±0.2 degrees 2 theta asmeasured by x-ray powder diffraction using an x-ray wavelength of 1.54Å.
 69. The compound of any one of claims 1, 2, and 67, wherein thecompound is characterized by a powder X-ray diffraction patterncomprising at least three peaks selected from 4.0, 4.4, 4.8, 6.9, 8.0,8.8, 9.6, 11.3, 12.4, 13.0, 13.1, 14.6, 14.9, 15.2, 16.6, 17.3, 17.4,17.9, and 19.5±0.2 degrees 2 theta as measured by x-ray powderdiffraction using an x-ray wavelength of 1.54 Å.
 70. The compound of anyone of claims 1, 2, and 67, wherein the compound is characterized by apowder X-ray diffraction pattern comprising at least five peaks selectedfrom 4.0, 4.4, 4.8, 6.9, 8.0, 8.8, 9.6, 11.3, 12.4, 13.0, 13.1, 14.6,14.9, 15.2, 16.6, 17.3, 17.4, 17.9, and 19.5±0.2 degrees 2 theta asmeasured by x-ray powder diffraction using an x-ray wavelength of 1.54Å.
 71. The compound of any one of claims 1, 2, and 67, wherein thecompound is characterized by a powder X-ray diffraction patterncomprising at least seven peaks selected from 4.0, 4.4, 4.8, 6.9, 8.0,8.8, 9.6, 11.3, 12.4, 13.0, 13.1, 14.6, 14.9, 15.2, 16.6, 17.3, 17.4,17.9, and 19.5±0.2 degrees 2 theta as measured by x-ray powderdiffraction using an x-ray wavelength of 1.54 Å.
 72. The compound of anyone of claims 1, 2, and 67, wherein the compound is characterized by apowder X-ray diffraction pattern comprising peaks at 4.0, 4.4, 4.8, 6.9,8.0, 8.8, 9.6, 11.3, 12.4, 13.0, 13.1, 14.6, 14.9, 15.2, 16.2, 16.4,16.6, 17.3, 17.4, 17.9, and 19.5±0.2 degrees 2 theta as measured byx-ray powder diffraction using an x-ray wavelength of 1.54 Å.
 73. Thecompound of any one of claims 1, 2, and 67, wherein the compound ischaracterized by the powder X-ray diffraction pattern substantially asshown in FIG. 18 as measured by x-ray powder diffraction using an x-raywavelength of 1.54 Å.
 74. The compound of any one of claims 1, 2, and67-73, wherein the compound is characterized by a differential scanningcalorimetry thermogram comprising an endotherm with an onset of about91° C.
 75. The compound of any one of claims 1, 2, and 67-74, whereinthe compound is characterized by having a thermogravimetric analysisthermogram comprising an approximate 11% weight loss when heated fromabout 39° C. to about 160° C.
 76. The compound of any one of claims67-75, wherein the compound is substantially pure.
 77. A pharmaceuticalcomposition comprising the compound of any one of claims 67-76 and apharmaceutically acceptable excipient.
 78. The compound of claim 1 or 2,wherein the compound is a crystalline solvate form of Compound
 1. 79.The compound of claim 78, wherein the compound is a solvate withtetrahydrofuran, acetonitrile, methyl ethylketone, ethyl acetate,dichloromethane, acetone, p-dioxane, methanol, isopropyl alcohol, orethanol.
 80. A compound, wherein the compound is an amorphous form of6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidin-2(1H)-one(Compound 1) or an atropisomer thereof.
 81. The compound of claim 80,wherein the compound is the M atropisomer of Compound
 1. 82. Thecompound of claims 80 or 81, wherein the compound is characterized bythe powder X-ray diffraction pattern substantially as shown in FIG. 5 asmeasured by x-ray powder diffraction using an x-ray wavelength of 1.54Å.
 83. The compound of any one of claims 80-82, wherein the compound ischaracterized by a differential scanning calorimetry thermogramcomprising an endotherm with an onset of about 144° C.
 84. The compoundof any one of claims 80-83, wherein the compound is characterized by athermogravimetric analysis thermogram comprising a weight loss of about1.5% when heated from about 25° C. to about 275° C.
 85. The compound ofany one of claims 80-84, wherein the compound is characterized by ¹⁹Fsolid state NMR comprising peaks at approximately −86, −96, −116, −127,−146, and −156 ppm.
 86. The compound of any one of claims 80-85, whereinthe compound is characterized by ¹⁹F solid state NMR substantially asdepicted in FIG.
 4. 87. The compound of any one of claims 80-86, whereinthe compound is substantially pure.
 88. A pharmaceutical compositioncomprising the compound of any one of claims 80-87 and apharmaceutically acceptable excipient.
 89. A pharmaceutical compositioncomprising (1) the compound of any one of claims 4-18, (2) the compoundof any one of claims 43-54, (3) the compound of any one of claims 57-64,(4) the compound of any one of claims 67-75, or (5) the compound of anyone of claims 80-86, or any mixtures thereof, and a pharmaceuticallyacceptable excipient.